Heterocyclic inhibitors of ERK2 and uses thereof

ABSTRACT

Described herein are compounds that are useful as protein kinase inhibitors having the formula: 
                         
wherein Z 1  and Z 2  are each independently nitrogen or CH and Ring A, T m R 1 , QR 2 , U n R 3 , and Sp are as described in the specification. The compounds are especially useful as inhibitors of ERK2 and for treating diseases in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, diabetes, and cardiovascular disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/071,699, filed Feb. 8, 2002 now U.S. Pat. No. 6,743,791, which claimspriority to U.S. Provisional Application Ser. No. 60/267,818 filed Feb.9, 2001 and U.S. Provisional Application Ser. No. 60/328,768 filed Oct.12, 2001, the entirety of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention is in the field of medicinal chemistry and relatesto pyrazole compounds that are protein kinase inhibitors, especiallyinhibitors of ERK, compositions containing such compounds and methods ofuse. The compounds are useful for treating cancer and other diseasesthat are alleviated by protein kinase inhibitors.

BACKGROUND OF THE INVENTION

Mammalian mitogen-activated protein (MAP)1 kinases are serine/threoninekinases that mediate intracellular signal transduction pathways (Cobband Goldsmith, 1995, J Biol. Chem., 270, 14843; Davis, 1995, Mol.Reprod. Dev. 42, 459). Members of the MAP kinase family share sequencesimilarity and conserved structural domains, and include the ERK2(extracellular signal regulated kinase), JNK (Jun N-terminal kinase),and p38 kinases. JNKs and p38 kinases are activated in response to thepro-inflammatory cytokines TNF-alpha and interleukin-1, and by cellularstress such as heat shock, hyperosmolarity, ultraviolet radiation,lipopolysaccharides and inhibitors of protein synthesis (Derijard etal., 1994, Cell 76, 1025; Han et al., 1994, Science 265, 808; Raingeaudet al., 1995, J Biol. Chem. 270, 7420; Shapiro and Dinarello, 1995,Proc. Natl. Acad. Sci. USA 92, 12230). In contrast, ERKs are activatedby mitogens and growth factors (Bokemeyer et al. 1996, Kidney Int. 49,1187).

ERK2 is a widely distributed protein kinase that achieves maximumactivity when both Thr183 and Tyr185 are phosphorylated by the upstreamMAP kinase kinase, MEK1 (Anderson et al., 1990, Nature 343, 651; Crewset al., 1992, Science 258, 478). Upon activation, ERK2 phosphorylatesmany regulatory proteins, including the protein kinases Rsk90 (Bjorbaeket al., 1995, J. Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al.,1994, Cell 78, 1027), and transcription factors such as ATF2 (Raingeaudet al., 1996, Mol. Cell Biol. 16, 1247), Elk-1 (Raingeaud et al. 1996),c-Fos (Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952), andc-Myc (Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2is also a downstream target of the Ras/Raf dependent pathways (Moodie etal., 1993, Science 260, 1658) and may help relay the signals from thesepotentially oncogenic proteins. ERK2 has been shown to play a role inthe negative growth control of breast cancer cells (Frey and Mulder,1997, Cancer Res. 57, 628) and hyperexpression of ERK2 in human breastcancer has been reported (Sivaraman et al., 1997, J Clin. Invest. 99,1478). Activated ERK2 has also been implicated in the proliferation ofendothelin-stimulated airway smooth muscle cells, suggesting a role forthis kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol.Biol. 16, 589).

Aurora-2 is a serine/threonine protein kinase that has been implicatedin human cancer, such as colon, breast and other solid tumors. Thiskinase is believed to be involved in protein phosphorylation events thatregulate the cell cycle. Specifically, Aurora-2-may play a role incontrolling the accurate segregation of chromosomes during mitosis.Misregulation of the cell cycle can lead to cellular proliferation andother abnormalities. In human colon cancer tissue, the aurora-2 proteinhas been found to be overexpressed. See Bischoff et al., EMBO J., 1998,17, 3052–3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635–1646;Kimura et al., J. Biol. Chem., 1997, 272, 13766–13771.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinasecomprised of α and β isoforms that are each encoded by distinct genes[Coghlan et al., Chemistry & Biology, 7, 793–803 (2000); Kim and Kimmel,Curr. Opinion Genetics Dev., 10, 508–514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role. GSK-3 has been found tophosphorylate and modulate the activity of a number of regulatoryproteins. These proteins include glycogen synthase which is the ratelimiting enzyme necessary for glycogen synthesis, the microtubuleassociated protein Tau, the gene transcription factor β-catenin, thetranslation initiation factor e1F2B, as well as ATP citrate lyase, axin,heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. These diverseprotein targets implicate GSK-3 in many aspects of cellular metabolism,proliferation, differentiation and development.

In a GSK-3 mediated pathway that is relevant for the treatment of typeII diabetes, insulin-induced signaling leads to cellular glucose uptakeand glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93,8455–9 (1996); Cross et al., Biochem. J., 303, 21–26 (1994); Cohen,Biochem. Soc. Trans., 21, 555–567 (1993); Massillon et al., Biochem J.299, 123–128 (1994)]. However, in a diabetic patient where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[WO 00/38675]. Therapeutic inhibitors of GSK-3 therefore are consideredto be useful for treating diabetic patients suffering from an impairedresponse to insulin.

GSK-3 activity has also been associated with Alzheimer's disease. Thisdisease is characterized by the well-known β-amyloid peptide and theformation of intracellular neurofibrillary tangles. The neurofibrillarytangles contain hyperphosphorylated Tau protein where Tau isphosphorylated on abnormal sites. GSK-3 has been shown to phosphorylatethese abnormal sites in cell and animal models. Furthermore, inhibitionof GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells[Lovestone et al., Current Biology 4, 1077–86 (1994); Brownlees et al.,Neuroreport 8, 3251–55 (1997)]. Therefore, it is believed that GSK-3activity may promote generation of the neurofibrillary tangles and theprogression of Alzheimer's disease.

Another substrate of GSK-3 is β-catenin which is degradated afterphosphorylation by GSK-3. Reduced levels of β-catenin have been reportedin schizophrenic patients and have also been associated with otherdiseases related to increase in neuronal cell death [Zhong et al.,Nature, 395, 698–702 (1998); Takashima et al., PNAS, 90, 7789–93 (1993);Pei et al., J. Neuropathol. Exp, 56, 70–78 (1997)].

As a result of the biological importance of GSK-3, there is currentinterest in therapeutically effective GSK-3 inhibitors. Small moleculesthat inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) andWO 00/38675 (SmithKline Beecham)].

Aryl substituted pyrroles are known in the literature. In particular,tri-aryl pyrroles (U.S. Pat. No. 5,837,719) have been described ashaving glucagon antagonist activity. 1,5-Diarylpyrazoles have beendescribed as p38 inhibitors (WO 9958523).

There is a high unmet medical need to develop new therapeutic treatmentsthat are useful in treating the various conditions associated with ERK2activation. For many of these conditions the currently availabletreatment options are inadequate.

Accordingly, there is great interest in new and effective inhibitors ofprotein kinase, including ERK2 inhibitors, that are useful in treatingvarious conditions associated with protein kinase activation.

DESCRIPTION OF THE INVENTION

It has now been found that compounds of this invention and compositionsthereof are effective as protein kinase inhibitors, especially asinhibitors of ERK2. These compounds have the general formula I:

or a pharmaceutically acceptable derivative thereof, wherein:,

-   -   Sp is a spacer group comprising a 5-membered heteroaromatic        ring, wherein Ring A and QR² are attached to Sp at non-adjacent        positions; and wherein Sp has up to two R⁶ substituents,        provided that two substitutable carbon ring atoms in Sp are not        simultaneously substituted by R⁶;    -   Z¹ and Z² are each independently selected from N or CH;    -   T and Q are each an independently selected linker group;    -   U is selected from —NR⁷—, —NR⁷CO—, —NR⁷CONR⁷—, —NR⁷CO₂—, —O—,        —CONR⁷—, —CO—, —CO₂—, —OC(O)—, —NR⁷SO₂—, —SO₂NR⁷—, —NR⁷SO₂NR⁷—,        or —SO₂—;    -   m and n are each independently selected from zero or one;    -   R¹ is selected from hydrogen, CN, halogen, R, N(R⁷)₂, OR, or OH;    -   R² is selected from —(CH₂)_(y)R⁵, —(CH₂)_(y)CH(R⁵)₂,        —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, —N(R⁴)₂, or —NR⁴(CH₂)_(y)N(R⁴)₂;    -   y is 0–6;    -   R³ is selected from R⁷, R, —(CH₂)_(y)CH(R⁸)R, CN,        —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, or —(CH₂)_(y)CH(R⁸)N(R⁴)₂;    -   each R is independently selected from an optionally substituted        group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl        ring having 5–10 ring atoms, or a heterocyclyl ring having 3–10        ring atoms;    -   each R⁴ is independently selected from R, R⁷, —COR⁷, —CO₂R,        —CON(R⁷)₂, —SO₂R⁷, —(CH₂)_(y)R⁵, or —(CH₂)_(y)CH(R⁵)₂;    -   each R⁵ is independently selected from R, OR, CO₂R,        (CH₂)_(y)N(R⁷)₂, N(R⁷)₂, OR⁷, SR⁷, NR⁷COR⁷, NR⁷CON(R⁷)₂;        CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, or SO₂N(R⁷)₂;    -   each R⁶ is independently selected from R⁷, F, Cl,        (CH₂)_(y)N(R⁷)₂, N(R⁷)₂, OR⁷, SR⁷, NR⁷COR⁷, NR⁷CON(R⁷)₂,        CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, or SO₂N(R⁷)₂;    -   each R⁷ is independently selected from hydrogen or an optionally        substituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen        are taken together with the nitrogen to form a 5–8 membered        heterocyclyl or heteroaryl ring;    -   R⁸ is selected from R, (CH₂)_(w)OR⁷, (CH₂)_(w)N(R⁴)₂, or        (CH₂)_(w)SR⁷; and    -   each w is independently selected from 0–4.

As used herein, the following definitions shall apply unless otherwiseindicated. The phrase “optionally substituted” is used interchangeablywith the phrase “substituted or unsubstituted” or with the term“(un)substituted.” Unless otherwise indicated, an optionally'substitutedgroup may have a substituent at each substitutable position of thegroup, and each substitution is independent of the other.

The term “aliphatic” or “aliphatic group” as used herein means astraight-chain or branched C₁–C₁₂ hydrocarbon chain that is completelysaturated or that contains one or more units of unsaturation, or amonocyclic C₃–C₈ hydrocarbon or bicyclic C₈–C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic (also referred to herein as “carbocycle” or“cycloalkyl”), that has a single point of attachment to the rest of themolecule wherein any individual ring in said bicyclic ring system has3–7 members. For example, suitable aliphatic groups include, but are notlimited to, linear or branched or alkyl, alkenyl, alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and“alkoxycarbonyl”, used alone or as part of a larger moiety includes bothstraight and branched chains containing one to twelve carbon atoms. Theterms “alkenyl” and “alkynyl” used alone or as part of a larger moietyshall include both straight and branched chains containing two to twelvecarbon atoms.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes anyoxidized form of nitrogen and sulfur, and the quaternized form of anybasic nitrogen. Also the term “nitrogen” includes a substitutablenitrogen of a heterocyclic ring. As an example, in a saturated orpartially unsaturated ring having 0–3 heteroatoms selected from oxygen,sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic and whereineach ring in the system contains 3 to 7 ring members. The term “aryl”may be used interchangeably with the term “aryl ring”.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans non-aromatic, monocyclic, bicyclic or tricyclic ring systemshaving five to fourteen ring members in which one or more ring membersis a heteroatom, wherein each ring in the system contains 3 to 7 ringmembers.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Suitable substituents on theunsaturated carbon atom of an aryl, heteroaryl, aralkyl, orheteroaralkyl group are selected from halogen, —R°, —OR°, —SR°,1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy),phenyl (Ph), Ph substituted with R°, —O(Ph), O-(Ph) substituted with R°,—CH₂(Ph), —CH₂(Ph) substituted with R°, —CH₂CH₂(Ph), —CH₂CH₂(Ph)substituted with R°, —NO₂, —CN, —N((R°)₂, —NR°C(O)R°, —NR°C(O)N(R)₂,—NR°CO₂R°, —NR°NR°C(O)R°, —NR°NR°C(O)N(R°)₂, —NR°NR°CO₂R°, —C(O)C(O)R°,—C(O)CH₂C(O)R°, —CO₂R°, —C(O)R°, —C(O)N(R°)₂, —OC(O)N(R°)₂, —S(O)₂R°,—SO₂N(R°)₂, —S(O)R°, —NR°SO₂N(R°)₂, —NR°SO₂R°, —C(═S)N(R°)₂,—C(═NH)—N(R°)₂, —(CH₂)_(y)NHC(O)R°, or —(CH₂)_(y)NHC(O)CH(V—R°)(R°),wherein each R° is independently selected from hydrogen, optionallysubstituted C₁₋₆ aliphatic, an unsubstituted 5–6 membered heteroaryl orheterocyclic ring, phenyl (Ph), —O(Ph), or —CH₂(Ph)—CH₂(Ph), wherein yis 0–6; and V is a&linker group. Substituents on the aliphatic group ofR° are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, OH, O—(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), —O(halo C₁₋₄ aliphatic), or halo C₁₋₄ aliphatic.

An aliphatic group or a non-aromatic heterocyclic ring may contain oneor more substituents. Suitable substituents on the saturated carbon ofan aliphatic group or of a non-aromatic heterocyclic ring are selectedfrom those listed above for the unsaturated carbon of an aryl orheteroaryl-group and the following: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═N—,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic. Substituents on the aliphatic group of R* are selected fromNH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic,OH, O—(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄aliphatic), or halo C₁₋₄ aliphatic.

Substituents on the nitrogen of a non-aromatic heterocyclic ring areselected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or—NR⁺SO₂R⁺; wherein R⁺is hydrogen, an optionally substituted C₁₋₆aliphatic, optionally substituted phenyl (Ph), optionally substituted—O(Ph), optionally substituted —CH₂(Ph), optionally substituted—CH₂CH₂(Ph), or an unsubstituted 5–6 membered heteroaryl or heterocyclicring. Substituents on the aliphatic group or the phenyl ring of R⁺ areselected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O—(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic),—O(halo C₁₋₄ aliphatic), or halo C₁₋₄ aliphatic.

The term “alkylidene chain” refers to an optionally substituted,straight or branched carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group.

The term “spacer group” refers to a group that separates and orientsother parts of the molecule attached thereto, such that the compoundfavorably interacts with functional groups in the active site of anenzyme. As used herein, the spacer group separates and orients ring Aand QR² within the active site such that they may form favorableinteractions with functional groups which exist within the active siteof the ERK2 enzyme. When the spacer group is a 5-membered heteroaromaticring, ring A and QR² are attached at non-adjacent positions “B” and “C”,and the 5-membered ring is attached to ring A at point “D” and to QR² atpoint “E” as illustrated below.

Preferably, the distance between “D” and “C” is 3.7 Å, the distancebetween “D” and “E” is 5.0 Å, the distance between “B” and “C” is 2.2 Å,and the distance between “B” and “E” is 3.5 Å, wherein each of the abovedescribed distances is plus/minus 0.2 Å.

The spacer group itself may also form additional interactions within theactive site to further enhance inhibitory activity of the compounds. Forexample, when Sp is a pyrrole the pyrrole-NH may form an additionalhydrogen bond within the active site of the ERK2 enzyme.

The term “linker group” means an organic moiety that connects two partsof a compound. Linkers are typically comprised of an atom such as oxygenor sulfur, a unit such as —NH—, —CH₂—, —CO—, or a chain of atoms, suchas an alkylidene chain. The molecular mass of a linker is typically inthe range of about 14 to 200. Examples of linkers include a saturated orunsaturated C₁₋₆ alkylidene chain which is optionally substituted, andwherein up to two saturated carbons of the chain are optionally replacedby —C(O)—, —C(O)C(O)—, —CONR⁷—, —CONR⁷NR⁷—, —CO₂—, OC(O)—, —NR⁷CO₂—,—O—, —NR⁷CONR⁷—, —OC(O)NR⁷—, —NR⁷NR⁷—, —NR⁷CO—, —S—, —SO—, —SO₂—, —NR⁷—,—SO₂NR⁷—, or —NR⁷SO₂—.

As used herein, linker group Q connects Sp with R². Q may also formadditional interactions within the ERK2 binding site to further enhancethe inhibitory activity of the compound. When Q is a carbonyl-containingmoeity such as —C(O)—, —CO₂—, —OC(O)—, —C(O)C(O)—, —CONH—, —CO₂NH—,—CONHNH—, —NHCO—, —OC(O)NH—, or —NHCO₂—, or a sulfonyl-containing moeitysuch as —SO₂—, —SO₂NH—, or —NHSO₂—, the carbonyl or sulfonyl oxygenforms a hydrogen-bond with lysine 54 in the ERK2 binding site. When Q isan NH-containing moeity such as —CH₂NH— or —NHNH—, the NH-group forms ahydrogen-bond with aspartic acid residue 167 in the ERK2 binding site.When Q is a hydrophobic group such as an alkyl chain, —O—, or —S—, Qforms additional hydrophobic interactions within the ERK2 binding site.

R² forms hydrophobic interactions within the binding site of ERK2,especially with the side-chain carbons of lysine 54 and aspartic acid167. R² may also form hydrophobic interactions with the glycine-richloop which is made up of amino-acid residues 33–38. When R² issubstituted, the substituents may form further interactions within thebinding site to enhance the inhibitory activity of the compound. Forexample, when a substituent on R is a hydrogen-bond donor or ahydrogen-bond acceptor, said substituent forms a hydrogen bond withenzyme-bound water molecules that exist in the binding site.

As used herein, linker group T, when present, connects Sp with R¹. T mayalso form additional interactions within the ERK2 binding site tofurther enhance the inhibitory activity of the compound. When T iscarbonyl-containing such as —CO—, —CO₂—, —OCO—, —COCO—, —CONH—, —CO₂NH—,—CONHNH—, —NHCO—, or —NHCO₂—, or sulfonyl-containing such as —SO₂—,—SO₂NH—, or —NHSO₂—, the carbonyl or sulfonyl oxygen forms ahydrogen-bond with the NH of glutamine 105 in the ERK2 binding site.When T is NH-containing such as —CH₂NH— or —NHNH—, the NH-group forms ahydrogen-bond with the carbonyl of glutamine 105. When T is ahydrophobic group such as an alkyl chain, —O—, or —S—, T formsadditional hydrophobic interactions with the side-chain carbons ofglutamine 105 as well as isoleucine 84.

The binding interactions described herein between the compounds of thisinvention and the ERK2 binding-site have been determined by molecularmodeling programs that are known to those of ordinary skill in the art.These molecular modeling programs include QUANTA [Molecular Simulations,Inc., Burlington, Mass., 1992] and SYBYL [Molecular Modeling Software,Tripos Associates, Inc., St. Louis, Mo., 1992]. As used herein, theamino acid numbering for the ERK2 enzyme corresponds to the Swiss-Protdatabase entry for accession #P28482. The Swiss-Prot database is aninternational protein sequence database distributed by the EuropeanBioinformatics Institute (EBI) in Geneva, Switzerland. The database canbe found at www.ebi.ac.uk/swissprot.

The compounds of this invention are limited to those that are chemicallyfeasible and stable. Therefore, a combination of substituents orvariables in the compounds described above is permissible only if such acombination results in a stable or chemically feasible compound. Astable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

Compounds of formula I or salts thereof may be formulated intocompositions. In a preferred embodiment, the composition is apharmaceutically acceptable composition. In one embodiment, thecomposition comprises an amount of the protein kinase inhibitoreffective to inhibit a protein kinase, particularly ERK-2, in abiological sample or in a patient. In another embodiment, compounds ofthis invention and pharmaceutical compositions thereof, which comprisean amount of the protein kinase inhibitor effective to treat or preventan ERK-2-mediated condition and a pharmaceutically acceptable carrier,adjuvant, or vehicle, may be formulated for administration to a patient.

The term “patient” includes human and veterinary subjects.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; preparations of an enzymesuitable for in vitro assay; biopsied material obtained from a mammal orextracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

Another aspect of this invention relates to a method of treating orpreventing an ERK-2-mediated disease, which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable comprising said compound.

The term “ERK-2-mediated condition” or “disease”, as used herein, meansany disease or other deleterious condition in which ERK-2 is known toplay a role. The term “ERK-2-mediated condition” or “disease” also meansthose diseases or conditions that are alleviated by treatment with anERK-2 inhibitor. Such conditions include, without limitation, cancer,stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases. The term “cancer” includes, but is not limitedto the following cancers: breast, ovary, cervix, prostate, testis,genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma,stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cellcarcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon,adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx,small intestine, colon-rectum, large intestine, rectum, brain andcentral nervous system, and leukemia.

The present method is especially useful for treating a disease that isalleviated by the use of an inhibitor of ERK2 or other protein kinases.Although the present compounds were designed as ERK2 inhibitors, it hasbeen found that certain compounds of this invention also inhibit otherprotein kinases such as GSK3, Aurora2, Lck, CDK2, and AKT3.

Another aspect of the invention relates to inhibiting ERK-2 activity ina biological sample, which method comprises contacting the biologicalsample with a compound of formula I, or a pharmaceutically acceptablecomposition comprising said compound.

Another aspect of this invention relates to a method of inhibiting ERK-2activity in a patient, which method comprises administering to thepatient a compound of formula I or a pharmaceutically acceptablecomposition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease, which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable comprising said compound.

The term “Aurora-2-mediated condition” or “disease”, as used herein,means any disease or other deleterious condition in which Aurora isknown to play a role. The term “Aurora-2-mediated condition” or“disease” also means those diseases or conditions that are alleviated bytreatment with an Aurora-2 inhibitor. Such conditions include, withoutlimitation, cancer. The term “cancer” includes, but is not limited tothe following cancers: colon, breast, stomach, and ovarian.

Another aspect of the invention relates to inhibiting Aurora-2 activityin a biological sample, which method comprises contacting the biologicalsample with a compound of formula I, or a pharmaceutically acceptablecomposition comprising said compound.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula I or a pharmaceutically acceptablecomposition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease, which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable comprising said compound.

The term “GSK-3-mediated condition” or “disease”, as used herein, meansany disease or other deleterious condition or state in which GSK-3 isknown to play a role. Such diseases or conditions include, withoutlimitation, diabetes, Alzheimer's disease, Huntington's Disease,Parkinson's Disease, AIDS-associated dementia, amyotrophic lateralsclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycetehypertrophy, reperfusion/ischemia, and baldness.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable thereof. This method is especially usefulfor diabetic patients. Another method relates to inhibiting theproduction of hyperphosphorylated Tau protein, which is useful inhalting or slowing the progression of Alzheimer's disease. Anothermethod relates to inhibiting the phosphorylation of β-catenin, which isuseful for treating schizophrenia.

Another aspect of the invention relates to inhibiting GSK-3 activity ina biological sample, which method comprises contacting the biologicalsample with a compound of formula I.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula I or a pharmaceutically acceptablecomposition comprising said compound.

Inhibition of ERK2, Aurora2, CDK2, GSK-3, Lck, or AKT3 kinase activityin a biological sample is useful for a variety of purposes which areknown to one of skill in the art. Examples of such purposes include; butare not limited to, blood transfusion, organ-transplantation, biologicalspecimen storage, and biological assays.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that may beadministered to a patient, together with a compound of this invention,and which does not destroy the pharmacological activity thereof.

The amount effective to inhibit protein kinase, for example, Aurora-2and GSK-3, is one that measurably inhibits the kinase activity wherecompared to the activity of the enzyme in the absence of an inhibitor.Any method may be used to determine inhibition, such as, for example,the Biological Testing -Examples described below.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids;such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives of the compounds of this invention may also beemployed in compositions to treat or prevent the above-identifieddiseases or disorders.

A “pharmaceutically acceptable derivative” means any pharmaceuticallyacceptable salt, ester, salt of an ester or other derivative of acompound of this invention which, upon administration to a recipient, iscapable of providing, either directly or indirectly, a compound of thisinvention or an inhibitorily active metabolite or residue thereof.Particularly favored derivatives are those that increase thebioavailability of the compounds of this invention when such compoundsare administered to a patient (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood) or which enhancedelivery of the parent compound to a biological compartment (e.g., thebrain or lymphatic system) relative to the parent species.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodiumand potassium), alkaline earth metal (e.g., magnesium), ammonium andN⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternizationof any basic nitrogen-containing groups of the compounds disclosedherein. Water or oil-soluble or dispersible products may be obtained bysuch quaternization.

The amount of the protein kinase inhibitor that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the patient treated and the particular mode of administration.Preferably, the compositions should be formulated so that a dosage ofbetween 0.01–100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of the inhibitor will also depend upon the particular compound inthe composition.

The kinase inhibitors of this invention or pharmaceutical compositionsthereof may also be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents and catheters. Vascular stents, for example,have been used to overcome restenosis (re-narrowing of the vessel wallafter injury). However, patients using stents or other implantabledevices risk clot formation or platelet activation. These unwantedeffects may be prevented or mitigated by pre-coating the device with apharmaceutically acceptable composition comprising a kinase inhibitor.Suitable coatings and the general preparation of coated implantabledevices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and5,304,121. The coatings are typically biocompatible polymeric materialssuch as a hydrogel polymer, polymethyldisiloxane, polycaprolactone,polyethylene glycol, polylactic acid, ethylene vinyl acetate, andmixtures thereof. The coatings may optionally be further covered by asuitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol,phospholipids or combinations thereof to impart controlled releasecharacteristics in the composition. Implantable devices coated with akinase inhibitor of this invention are another embodiment of the presentinvention.

Depending upon the particular protein kinase-mediated condition to betreated or prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may be administeredtogether with the inhibitors of this invention. For example, in thetreatment of cancer other chemotherapeutic agents or otheranti-proliferative agents may be combined with the protein kinaseinhibitors of this invention to treat cancer. These agents include,without limitation, adriamycin, dexamethasone, vincristine,cyclophosphamide, fluorouracil, topotecan, taxol, interferons, andplatinum derivatives.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation, agents for treating diabetessuch as insulin or insulin analogues, in injectable or inhalation form,glitazones, alpha glucosidase inhibitors, biguanides, insulinsensitizers, and sulfonyl ureas; anti-inflammatory agents such ascorticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; immunomodulatory and immunosuppressive agents such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

Those additional agents may be administered separately from the proteinkinase inhibitor-containing composition, as part of a multiple dosageregimen. Alternatively, those agents may be part of a single dosageform, mixed together with the protein kinase inhibitor of this inventionin a single composition.

Compounds of this invention may exist in alternative tautomeric forms.Unless otherwise indicated, the representation of either tautomer ismeant to include the other.

Accordingly, the present invention relates to compounds of formula Iwherein Ring A is a pyridine (II), pyrimidine (III), or triazine (IV)ring as shown below:

or a pharmaceutically acceptable derivative thereof, wherein Sp,T_(m)R¹, R², U_(n)R³, Q, and T are as described above.

Examples of suitable Sp groups of formula I include pyrrole (a),imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f),1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), asshown below:

wherein each of a through j is optionally substituted with R⁶.

Preferred T_(m)R¹ groups of formula I are selected from hydrogen,N(R⁴)₂, OH, 3–6 membered carbocyclyl, or an optionally substituted groupselected from C₁₋₆ aliphatic or a 5–6 membered aryl or heteroaryl ring.When R¹ is an optionally substituted phenyl or aliphatic group,preferred substituents on the phenyl or aliphatic group are R⁷, halo,nitro, alkoxy, and amino. Preferred T_(m)R¹ groups are methyl, ethyl,propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, NH₂, NHCH₃, NHAc,NHC(O)NHCH₃, and CH₂NHCH₃. More preferred T_(m)R¹ groups of formula Iare those listed in Table 1 below.

Preferred R³ groups of formula I are hydrogen, carbocyclyl, —CH(R⁸)R, oran optionally substituted group selected from C₁₋₄ aliphatic, 3–6membered heterocyclic, or a 5–6 membered aryl or heteroaryl ring.Examples of such groups include methyl, ethyl, propyl, cyclopropyl,cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. WhenR³ is optionally substituted phenyl, preferred substituents on thephenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl,OCF₃, OH, SO₂NH₂, and methylene dioxy. When R³ is —CH(R⁸)R, examples ofsuch groups include —CH(CH₂OH)phenyl, —CH(CH₂OH)ethyl, —CH(CH₂OH)₂,—CH(CH₂OH)isopropyl, and —CH(CH₂OH)CH₂cyclopropyl. Preferred U_(n)groups, when present, are —CH₂—, —O—, —NR⁷—, —NHCO—, and —NHCO₂—. Morepreferred U_(n)R³ groups of formula I are those listed in Table 1 below.

When R² is R⁵, preferred R⁵ groups are pyrrolidin-1-yl, morpholin-4-yl,piperidin-1-yl, and piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl,4-phenyl-piperazine-1-yl, wherein each group is optionally substituted.When R² is (CH₂)_(y)R⁵, (CH₂)_(y)CH(R⁵)₂, or —N(R⁴)₂, preferred R⁵groups are further selected from pyridin-3-yl, pyridin-4-yl, imidazolyl,furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl,cyclohexyl, phenyl, benzyl, —CH₂OH, —(CH₂)₂OH, and isopropyl, whereineach group is optionally substituted. Preferred substituents on R⁵ are—OH, pyridyl, piperidinyl, and optionally substituted phenyl. When R² is—(CH₂)_(y)CH(R⁸)CH(R⁵)₂, preferred R⁸ groups are R⁷ and OR⁷ such as OHand CH₂OH and preferred R⁵ are as described above. Preferred—(CH₂)_(y)CH(R⁸)CH(R⁵)₂ groups of formula I are —CH(OH)CH(OH)phenyl and—CH(Me)CH(OH)phenyl. Other preferred —QR² groups are those listed inTable 1 below.

Preferred compounds of formula I are those having one or more, morepreferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, or an optionally        substituted group selected from C₁₋₄ aliphatic, 3–6 membered        heterocyclic, or a 5–6 membered aryl or heteroaryl ring;    -   (b) T_(m)R¹ is hydrogen, amino, OH, 3–6-membered carbocyclyl, or        an optionally substituted group selected from C₁₋₆ aliphatic or        a 5–6 membered aryl or heteroaryl ring;    -   (c) Q is —CO—, —CO₂—, —CONH—, —SO₂—, —SO₂NH—, —OC(O)NH—,        —C(O)ONH—, or —CONHNH—;    -   (d) R² is —NR⁴(CH₂)_(y)N(R⁴)₂, —(CH₂)_(y)R⁵, —(CH₂)_(y)CH(R⁵)₂,        or —(CH₂)_(y)CH(R⁸)CH(R⁵)₂;    -   (f) R⁴ is R, R⁷, or —(CH₂)_(y)CH(R⁵)₂; and    -   (g) R⁵ is an optionally substituted group selected from C₁₋₆        aliphatic, phenyl, 5–6 membered heteroaryl, or 5–6 membered        heterocyclyl.

More preferred compounds of formula I are those having one or more, morepreferably more than one, or most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is selected from hydrogen, methyl, ethyl, propyl,        cyclopropyl, cyclohexyl, isopropyl, —CH(CH₂OH)phenyl,        —CH(CH₂OH)ethyl, —CH(CH₂OH)₂, —CH(CH₂OH)isopropyl,        —CH(CH₂OH)CH₂cyclopropyl, or an optionally substituted phenyl,        benzyl, or isoxazolyl group;    -   (b) T_(m)R¹ is selected from optionally substituted phenyl,        methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH,        OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃;    -   (c) Q is —CO—, —CONH—, —SO₂—, or —SO₂NH—;    -   (d) R² is —(CH₂)_(y)R⁵, —(CH₂)_(y)CH(R⁵)₂, or        —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, wherein R⁸ is OH or CH₂OH; and    -   (e) R⁵ is —CH₂OH, —(CH₂)₂OH, isopropyl, or an optionally        substituted group selected from pyrrolidin-1-yl, morpholin-4-yl,        piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl,        4-phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-yl,        imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline,        tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl.

A preferred embodiment of this invention relates to compounds of formulaI′:

or a pharmaceutically acceptable derivative thereof, wherein:

-   -   Sp is a spacer group comprising a 5-membered heteroaromatic        ring, wherein Ring A and Q′R^(2′) are attached to Sp at        non-adjacent positions; and wherein Sp has up to two R⁶        substituents, provided that two substitutable carbon ring atoms        in Sp are not simultaneously substituted by R⁶;    -   Z¹ and Z² are each independently selected from N or CH;    -   Q′ is selected from —CO₂—, —C(O)NR⁷— or —SO₂NR⁷—;    -   T is a linker group;    -   U is selected from —NR⁷—, —NR⁷CO—, —NR⁷CONR⁷—, —NR⁷CO₂—, —O—,        —CONR⁷—, —CO—, —CO₂—, —OC(O)—, —NR⁷SO₂—, —SO₂NR⁷—, —NR SO₂NR⁷—,        or —SO₂—;    -   m and n are each independently selected from zero or one;    -   R′ is selected from hydrogen, CN, halogen, R, N(R⁷)₂, OR, or OH;    -   R^(2′) is selected from —(CH₂)_(y)CH(R⁵)₂ or        —(CH₂)_(y)CH(R⁸)CH(R⁵)₂;    -   y is 0–6;    -   R³ is selected from R⁷, R, —(CH₂)_(y)CH(R⁸)R, CN,        —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, or —(CH₂)_(y)CH(R⁸)N(R⁴)₂;    -   each R is independently selected from an optionally substituted        group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl        ring having 5–10 ring atoms, or a heterocyclyl ring having 3–10        ring atoms;    -   each R⁴ is independently selected from R, R⁷, —COR⁷, —CO₂R,        —CON(R⁷)₂, —SO₂R⁷, —(CH₂)_(y)R⁵, or —(CH₂)_(y)CH(R⁵)₂;    -   each R⁵ is independently selected from R, OR, CO₂R,        (CH₂)_(y)N(R⁷)₂, N(R⁷)₂, OR⁷, SR⁷, NR⁷COR⁷, NR⁷ CON(R⁷)₂,        CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, or SO₂N(R⁷)₂;    -   each R⁶ is independently selected from R⁷, F, Cl,        (CH₂)_(y)N(R⁷)₂, N(R⁷)₂, OR⁷, SR⁷, NR⁷COR⁷, NR⁷CON(R⁷)₂,        CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, or SO₂N(R⁷)₂;    -   each R⁷ is independently selected from hydrogen or an optionally        substituted Cl₆ aliphatic group, or two R⁷ on the same nitrogen        are taken together with the nitrogen to form a 5–8 membered        heterocyclyl or heteroaryl ring;    -   R⁸ is selected from R, (CH₂)_(w)OR⁷, (CH₂)_(w)N(R⁴)₂, or        (CH₂)_(w)SR⁷; and    -   each w is independently selected from 0–4.

Examples of suitable Sp groups of formula I′ include pyrrole (a),imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f),1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), asshown below:

wherein each of a through j is optionally substituted with R⁶.

Accordingly, the present invention relates to compounds of formula I′wherein Ring A is a pyridine (II′), pyrimidine (III′), or triazine (IV′)ring as shown below:

or a pharmaceutically acceptable derivative thereof, wherein Sp,T_(m)R¹, Q′R^(2′), and U_(n)R³ are as described above.

Preferred R⁵ groups of formula I′ are R or OR⁷. Examples of such groupsinclude OH, CH₂OH, carbocyclic, or optionally substituted 5 or6-membered aryl or heteroaryl rings, such as phenyl, pyridyl, andcyclohexyl. Preferred R⁸ groups of formula I′ are R and OR⁷, wherein Ris an optionally substituted group selected from C₁₋₄ aliphatic, 3–6membered heterocyclic, or a 5–6 membered aryl or heteroaryl ring.Examples of such groups include phenyl, methyl, ethyl, OH, and CH₂OH.Preferred substituents on the R⁵ aryl or heteroaryl ring are halogen,haloalkyl, OR°, and R°.

Preferred T_(m)R¹ groups of formula I′ are hydrogen, N(R⁴)₂, OH, 3–6membered carbocyclyl, or an optionally substituted group selected fromC₁₋₆ aliphatic or a 5–6 membered aryl or heteroaryl ring. When R¹ is anoptionally substituted phenyl or aliphatic group, preferred substituentson the phenyl or aliphatic group are R⁷, halo, nitro, alkoxy, and amino.Preferred T_(m)R¹ groups include methyl, ethyl, propyl, cyclopropyl,cyclohexyl, CH₂OCH₃, CH₂OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, and CH₂NHCH₃.More preferred T_(m)R¹ groups of formula I′ are those listed in Table 1below.

Preferred R³ groups of formula I′ are hydrogen, carbocyclyl, —CH(R⁸)R,or an optionally substituted group selected from C₁₋₄ aliphatic, 3–6membered heterocyclic, or a 5–6 membered aryl or heteroaryl ring.Examples of such groups include methyl, ethyl, propyl, cyclopropyl,cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. WhenR³ is optionally substituted phenyl, preferred substituents on thephenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl,OCF₃, OH, SO₂NH₂, and methylene dioxy. When R³ is —CH(R⁸)R, examples ofsuch groups include —CH(CH₂OH)phenyl, —CH(CH₂OH)ethyl, —CH(CH₂OH)₂,—CH(CH₂OH)isopropyl, and —CH(CH₂OH)CH₂cyclopropyl. Preferred U_(n)groups, when present, are —CH₂—, —O—, —NR⁷—, —NHCO—, and —NHCO₂—. Morepreferred U_(n)R³ groups of formula I′ are those listed in Table 1below.

Preferred compounds of formula I′ are those having one or more, morepreferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, or an optionally        substituted group selected from C₁₋₄ aliphatic, 3–6 membered        heterocyclic, or a 5–6 membered aryl or heteroaryl ring;    -   (b) T_(m)R¹ is hydrogen, amino, OH, 3–6 membered carbocyclyl, or        an optionally substituted group selected from C₁₋₆ aliphatic or        a 5–6 membered aryl or heteroaryl ring; and    -   (c) R⁵ is R or OR⁷, wherein R is carbocyclic, or an optionally        substituted 5 or 6-membered aryl or heteroaryl ring.

More preferred compounds of formula I′ are those having one or more,more preferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is selected from hydrogen, methyl, ethyl, propyl,        cyclopropyl, cyclohexyl, isopropyl, —CH(CH₂OH)phenyl,        —CH(CH₂OH)ethyl, —CH(CH₂OH)₂, —CH(CH₂OH)isopropyl,        —CH(CH₂OH)CH₂cyclopropyl, or an optionally substituted phenyl,        benzyl, or isoxazolyl group;    -   (b) T_(m)R¹ is selected from optionally substituted phenyl,        methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH,        OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and    -   (c) R⁵ is OH, CH₂OH, carbocyclic, or an optionally substituted        phenyl or pyridyl ring, and Q′ is C(O)NH.

Another preferred embodiment of this invention relates to compounds offormula I″:

or a pharmaceutically acceptable derivative thereof, wherein:

-   -   Sp is a spacer group comprising a 5-membered heteroaromatic        ring, wherein Ring A and C(O)NHCH[(CH₂)₁₋₂OH]R⁵ are attached to        Sp at non-adjacent positions; and wherein Sp has up to two R⁶        substituents, provided that two substitutable carbon ring atoms        in Sp are not simultaneously substituted by R⁶;    -   Z¹ and Z² are each independently selected from N or CH;    -   T is a linker group;    -   U is selected from —NR⁷—, —NR⁷CO—, —NR⁷CONR⁷—, —NR⁷CO₂—, —O—,        —CONR⁷—, —CO—, —CO₂—, —OC(O)—, —NR⁷SO₂—, —SO₂NR⁷—, —NR⁷SO₂NR⁷—,        or —SO₂—;    -   m and n are each independently selected from zero or one;    -   R¹ is selected from hydrogen, CN, halogen, R, N(R⁷)₂, OR, or OH;    -   R³ is selected from R⁷R, —(CH₂)_(y)CH(R⁸)R, CN,        —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, or —(CH₂)_(y)CH(R⁸)N(R⁴)₂;    -   each R is independently selected from an optionally substituted        group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl        ring having 5–10 ring atoms, or a heterocyclyl ring having 3–10        ring atoms;    -   each R⁴ is independently selected from R, R⁷, —COR⁷, —CO₂R,        —CON(R⁷)₂, —SO₂R⁷, —(CH₂)_(y)R⁵, or —(CH₂)_(y)CH(R⁵)₂,    -   each R⁵ is independently selected from R, OR, CO₂R,        (CH₂)_(y)N(R⁷)₂, N(R⁷)₂, OR⁷, SR⁷, NR⁷COR⁷, NR⁷CON(R⁷)₂,        CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, or SO₂N(R⁷)₂,    -   each R⁶ is independently selected from R⁷, F, Cl,        (CH₂)_(y)N(R⁷)₂, N(R⁷)₂, OR⁷, SR⁷, NR⁷COR⁷, NR⁷CON(R⁷)₂,        CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, or SO₂N(R⁷)₂;    -   each R⁷ is independently selected from hydrogen or an optionally        substituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen        are taken together with the nitrogen to form a 5–8 membered        heterocyclyl or heteroaryl ring;    -   R⁸ is selected from R, (CH₂)_(w)OR⁷, (CH₂)_(w)N(R⁴)₂, or        (CH₂)_(w)SR⁷; and    -   each w is independently selected from 0–4.

Examples of suitable Sp groups of formula I″ include pyrrole (a),imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f),1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), asshown below:

wherein each of a through j is optionally substituted with R⁶.

Accordingly, the present invention relates to compounds of formula I″wherein Ring A is a pyridine (II″), pyrimidine (III″), or triazine (IV″)ring as shown below:

or a pharmaceutically acceptable derivative thereof, wherein Sp,T_(m)R¹, U_(n)R³, and R⁵ are as described above.

Preferred T_(m)R¹ groups of formula I″ are hydrogen, N(R⁴)₂, OH, 3–6membered carbocyclyl, or an optionally substituted group selected fromC₁₋₆ aliphatic or a 5–6 membered aryl or heteroaryl ring. When R¹ is anoptionally substituted phenyl or aliphatic group, preferred substituentson the phenyl or aliphatic group are R⁷, halo, nitro, alkoxy, and amino.Examples of preferred T_(m)R¹ groups include methyl, ethyl, propyl,cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃,and CH₂NHCH₃. More preferred T_(m)R¹ groups of formula I″ are thoselisted below in Table 1.

Preferred R³ groups of formula I″ are hydrogen, carbocyclyl, —CH(R⁸)R,or an optionally substituted group selected from C₁₋₄ aliphatic, 3–6membered heterocyclic, or a 5–6 membered aryl or heteroaryl ring.Examples of such groups include methyl, ethyl, propyl, cyclopropyl,cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. WhenR³ is optionally substituted phenyl, preferred substituents on thephenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl,OCF₃, OH, SO₂NH₂, and methylene dioxy. When R³ is —CH(R⁸)R, examples ofsuch groups include —CH(CH₂OH)phenyl, —CH (CH₂OH)ethyl, —CH(CH₂OH)₂,—CH(CH₂OH)isopropyl, and —CH(CH₂OH)CH₂cyclopropyl. Preferred U_(n)groups, when present, are —CH₂—, —O—, —NR⁷—, —NHCO—, and —NHCO₂—. Morepreferred U_(n)R³ groups of formula I″ are those listed in Table 1below.

Preferred R⁵ groups of formula I″ are optionally substituted 6-memberedaryl, heteroaryl, and carbocyclic rings, such as phenyl, pyridyl, andcyclohexyl.

Preferred compounds of formula I″ are those having one or more, morepreferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, or an optionally        substituted group selected from C₁₋₄ aliphatic, 3–6 membered        heterocyclic, or a 5–6 membered aryl or heteroaryl ring;    -   (b) T_(m)R¹ is hydrogen, N(R⁴)₂, OH, 3–6 membered carbocyclyl,        or an optionally substituted group selected from C₁₋₆ aliphatic        or a 5–6 membered aryl or heteroaryl ring; and    -   (c) R⁵ is an optionally substituted 6-membered aryl, heteroaryl,        or carbocyclic ring.

More preferred compounds of formula I″ are those having one or more,more preferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is selected from hydrogen, methyl, ethyl, propyl,        cyclopropyl, cyclohexyl, isopropyl, —CH(CH₂OH)phenyl,        —CH(CH₂OH)ethyl, —CH(CH₂OH)₂, —CH(CH₂OH)isopropyl,        —CH(CH₂OH)CH₂cyclopropyl, or an optionally substituted phenyl or        benzyl group;    -   (b) T_(m)R¹ is selected from optionally substituted phenyl,        methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH,        NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and    -   (c) R⁵ is cyclohexyl or an optionally substituted phenyl or        pyridylring.

Another preferred embodiment of this invention relates to compounds offormula I°:

or a pharmaceutically acceptable derivative thereof, wherein:

-   -   Sp is a spacer group comprising a 5-membered heteroaromatic        ring, wherein Ring A and C(O)NNHCH(R⁸)CH(R⁵)₂ are attached to Sp        at non-adjacent positions; and wherein Sp has up to two R⁶        substituents, provided that two substitutable carbon ring atoms        in Sp are not simultaneously substituted by R⁶;    -   Z¹ and Z² are each independently selected from N or CH;    -   T is a linker group;    -   U is selected from —NR⁷—, —NR⁷CO—, —NR⁷CONR⁷—, —NR⁷CO₂—, —O—,        —CONR⁷—, —CO—, —CO₂—, —OC(O)—, —NR⁷SO₂—, —SO₂NR⁷—, —NR⁷SO₂NR⁷—,        or —SO₂—;    -   m and n are each independently selected from zero or one;    -   R¹ is selected from hydrogen, CN, halogen, R, N(R⁷)₂, OR, or OH;    -   y is 0–6;    -   R³ is selected from R⁷R, —(CH₂)_(y)CH(R⁸)R, CN,        —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, or —(CH₂)_(y)CH(R⁸)N(R⁴)₂;    -   each R is independently selected from an optionally substituted        group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl        ring having 5–10 ring atoms, or a heterocyclyl ring having 3–10        ring atoms;    -   each R⁵ is independently selected from R, OR, CO₂R,        (CH₂)_(y)N(R⁷)₂, N(R⁷)₂, OR⁷, SR⁷, NR⁷COR⁷, NR⁷CON(R⁷)₂;        CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, or SO₂N(R⁷)₂;    -   each R⁶ is independently selected from R⁷, F, Cl,        (CH₂)_(y)N(R⁷)₂, N(R⁷)₂, OR⁷, SR⁷, NR⁷COR⁷, NR⁷CON(R⁷)₂,        CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, or SO₂N(R⁷)₂;    -   each R⁷ is independently selected from hydrogen or an optionally        substituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen        are taken together with the nitrogen to form a 5–8 membered        heterocyclyl or heteroaryl ring;    -   R⁸ is selected from R, (CH₂)_(w)OR⁷, (CH₂)_(w)N(R⁴)₂, or        (CH₂)_(w)SR⁷; and    -   each w is independently selected from 0–4.

Examples of suitable Sp groups of formula I° include pyrrole (a),imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f),1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), asshown below:

wherein each of a through j is optionally substituted with R⁶.

Accordingly, the present invention relates to compounds of formula I°wherein Ring A is a pyridine (II°), pyrimidine (III°), or triazine (IV°)ring as shown below:

or a pharmaceutically acceptable derivative thereof, wherein Sp,T_(m)R¹, R⁵, U_(n)R³, and R⁸ are as described above.

Preferred R⁵ groups of formula I° are R or OR⁷. Examples of such groupsinclude OH, CH₂OH, carbocyclic, or optionally substituted5 or 6-memberedaryl or heteroaryl rings, such as phenyl, pyridyl, and cyclohexyl.Preferred R⁸ groups of formula I° are R and OR⁷; wherein R is anoptionally substituted group selected from C₁₋₄ aliphatic, 3–6 memberedheterocyclic, or a 5–6 membered aryl or heteroaryl ring. Examples ofsuch groups include phenyl, methyl, ethyl, OH, and CH₂OH. Preferredsubstituents on the R⁵ aryl or heteroaryl ring are halogen, haloalkyl,OR°, and R°.

Preferred T_(m)R¹ groups of formula I° are hydrogen, N(R⁴)₂, OH, 3–6membered carbocyclyl, or an optionally substituted group selected fromC₁₋₆ aliphatic or a 5–6 membered aryl or heteroaryl ring. When R¹ is anoptionally substituted phenyl or aliphatic group, preferred substituentson the phenyl or aliphatic group are R⁷, halo, nitro, alkoxy, and amino.More preferred T_(m)R¹ groups are methyl, ethyl, propyl, cyclopropyl,cyclohexyl, CH₂OCH₃, CH₂OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, and CH₂NHCH₃.Most preferred T_(m)R¹ groups of formula I° are those listed in Table 1below.

Preferred R³ groups of formula I° are hydrogen, carbocyclyl, —CH(R⁸)R,or an optionally substituted group selected from C₁₋₄ aliphatic, 3–6membered heterocyclic, or a 5–6 membered aryl or heteroaryl ring.Examples of such groups include methyl, ethyl, propyl, cyclopropyl,cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. WhenR³ is optionally substituted phenyl, preferred substituents on thephenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl,OCF₃, OH, SO₂NH₂, and methylene dioxy. When R³ is —CH(R⁸)R, examples ofsuch groups include —CH(CH₂OH)phenyl, —CH(CH₂OH)ethyl, —CH(CH₂OH)₂,—CH(CH₂OH)isopropyl, and —CH(CH₂OH)CH₂cyclopropyl. Preferred U_(n)groups, when present, are —CH₂—, —O—, —NR⁷—, —NHCO—, and —NHCO₂—. Morepreferred U_(n)R³ groups of formula I° are those listed in Table 1below.

Preferred compounds of formula I° are those having one or more, morepreferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, or an optionally        substituted group selected from C₁₋₄ aliphatic, 3–6 membered        heterocyclic, or a 5–6 membered aryl or heteroaryl ring;    -   (b) T_(m)R¹ is hydrogen, amino, OH, 3–6 membered carbocyclyl, or        an optionally substituted group selected from C₁₋₆ aliphatic or        a 5–6 membered aryl or heteroaryl ring; and    -   (c) R⁵ is R or OR⁷, wherein R is carbocyclic, or an optionally        substituted5 or 6-membered aryl or heteroaryl ring.

More preferred compounds of formula I° are those having one or more,more preferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is selected from hydrogen, methyl, ethyl, propyl,        cyclopropyl, cyclohexyl, isopropyl, —CH(CH₂OH)phenyl,        —CH(CH₂OH)ethyl, —CH(CH₂OH)₂, —CH(CH₂OH)isopropyl,        —CH(CH₂OH)CH₂cyclopropyl, or an optionally substituted phenyl,        benzyl, or isoxazolyl group;    -   (b) T_(m)R³ is selected from optionally substituted phenyl,        methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH,        OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and    -   (c) R⁵ is OH, CH₂OH, carbocyclic, or an optionally        substitutedphenyl or pyridyl ring.

A preferred embodiment relates to compounds of formula III-a:

or a pharmaceutically acceptable derivative thereof.

Preferred T_(m)R¹ groups of formula III-a are hydrogen, N(R⁴)₂, OH, 3–6membered carbocyclyl, or an optionally substituted group selected fromC₁₋₆ aliphatic or a 5–6 membered aryl or heteroaryl ring. When R¹ is anoptionally substituted phenyl or aliphatic group, preferred substituentson the phenyl or aliphatic group are R⁷, halo, nitro, alkoxy, and amino.Examples of such preferred T_(m)R¹ groups include methyl, ethyl, propyl,cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃,and CH₂NHCH₃. More preferred T_(m)R¹ groups of formula III-a are thoselisted in Table 1 below.

Preferred R³ groups of formula III-a are hydrogen, carbocyclyl,—CH(R⁸)R, or an optionally substituted group selected from C₁₋₄aliphatic, 3–6 membered heterocyclic, or a 5–6 membered aryl orheteroaryl ring. Examples of such groups include methyl, ethyl, propyl,cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, andisopropyl. When R³ is optionally substituted phenyl, preferredsubstituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl,Obenzyl, Ophenyl, OCF₃, OH, SO₂NH₂, and methylene dioxy. When R³ is—CH(R⁸)R, examples of such groups are —CH(CH₂OH)phenyl, —CH(CH₂OH)ethyl,—CH(CH₂OH)₂, —CH(CH₂OH)isopropyl, and —CH(CH₂OH)CH₂cyclopropyl.Preferred U_(n) groups, when present, are —CH₂—, —O—, —NR⁷—, —NHCO—, and—NHCO₂—. More preferred U_(n)R³ groups of formula III-a are those listedin Table 1 below.

When R² is R⁵, preferred R⁵ groups are pyrrolidin-1-yl, morpholin-4-yl,piperidin-1-yl, and piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl,4-phenyl-piperazine-1-yl, wherein each group is optionally substituted.When R² is (CH₂)_(y)R⁵, (CH₂)_(y)CH(R⁵)₂, or —N(R⁴)₂, preferred R⁵groups are pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl,1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl,phenyl, benzyl, —CH₂OH, —(CH₂)₂OH, and isopropyl, wherein each group isoptionally substituted. Preferred substituents on R⁵ are —OH, pyridyl,piperidinyl, and optionally substituted phenyl. When R² is—(CH₂)_(y)CH(R⁸)CH(R⁵)₂, preferred R³ groups are R⁷ and OR⁷ such as OHand CH₂OH. More preferred —QR² groups are those listed in Table 1 below.

Preferred compounds of formula III-a are those having one or more, morepreferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, or an optionally        substituted group selected from C₁₋₄ aliphatic, 3–6 membered        heterocyclic, or a 5–6 membered aryl or heteroaryl ring;    -   (b) T_(m)R¹ is hydrogen, N(R⁴)₂, OH, 3–6 membered carbocyclyl,        or an optionally substituted group selected from C₁₋₆ aliphatic        or a 5–6 membered aryl or heteroaryl ring;    -   (c) Q is —CO—, —CO₂—, —CONH—, —SO₂—, —SO₂NH—, —OC(O)NH—,        —C(O)ONH—, or —CONHNH—;    -   (d) R² is —NR⁴(CH₂)_(y)N(R⁴)₂, —(CH₂)_(y)R⁵, —(CH₂)_(y)CH(R⁵)₂,        or —(CH₂)_(y)CH(R⁸)CH(R⁵)₂;    -   (f) R⁴ is R, R⁷, or —(CH₂)_(y)CH(R⁵)₂; and    -   (g) R⁵ is an optionally substituted group selected from phenyl,        5–6 membered heteroaryl, or 5–6 membered heterocyclyl.

More preferred compounds of formula III-a are those having one or more,more preferably more than one, or most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is selected from hydrogen, methyl, ethyl, propyl,        cyclopropyl, cyclohexyl, isopropyl, —CH(CH₂OH)phenyl,        —CH(CH₂OH)ethyl, —CH(CH₂OH)₂, —CH(CH₂OH)isopropyl,        —CH(CH₂OH)CH₂cyclopropyl, or an optionally substituted phenyl or        benzyl group;    -   (b) T_(m)R¹ is selected from optionally substituted phenyl,        methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH,        OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃;    -   (c) Q is —CO—, —CONH—, —SO₂—, or —SO₂NH—;    -   (d) R² is —(CH₂)_(y)R⁵, —(CH₂)_(y)CH(R⁵)₂, or        —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, wherein R⁸ is OH or CH₂OH; and    -   (e) R⁵ is —CH₂OH, —(CH₂)₂OH, isopropyl, or an optionally        substituted group selected from pyrrolidin-1-yl, morpholin-4-yl,        piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl,        4-phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-yl,        imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline,        tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl.

Preferred compounds of formula III-a include those of formula III-a′:

or a pharmaceutically acceptable derivative thereof.

Preferred R⁵ groups of formula III-a′ are optionallysubstituted6-membered aryl, heteroaryl, and carbocyclic rings, such asphenyl, pyridyl, and cyclohexyl.

Preferred T_(m)R¹ groups of formula III-a′ are hydrogen, N(R⁴)₂, OH, 3–6membered carbocyclyl, or an optionally substituted group selected fromC₁₋₆ aliphatic or a 5–6 membered aryl or heteroaryl ring. When R′ is anoptionally substituted phenyl or aliphatic group, preferred substituentson the phenyl or aliphatic group are R⁷, halo, nitro, alkoxy, and amino.Preferred T_(m)R¹ groups are methyl, ethyl, propyl, cyclopropyl,cyclohexyl, CH₂OCH₃, CH₂OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, CH₂NHCH₃, andthose listed in Table 1 below.

Preferred R³ groups of formula III-a′ are hydrogen, carbocyclyl,—CH(R⁸)R, or an optionally substituted group selected from C₁₋₄aliphatic, 3–6 membered heterocyclic, or a 5–6 membered aryl orheteroaryl ring. Examples of such groups include methyl, ethyl, propyl,cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, andisopropyl. When R³ is optionally substituted phenyl, preferredsubstituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl,Obenzyl, Ophenyl, OCF₃, OH, SO₂NH₂, and methylene dioxy, When R³ is—CH(R⁸)R, examples of such groups include —CH(CH₂OH)phenyl,—CH(CH₂OH)ethyl; —CH(CH₂OH)₂, —CH(CH₂OH) isopropyl, and—CH(CH₂OH)CH₂cyclopropyl. Preferred U_(n) groups, when present, are—CH₂—, —O—, —NR⁷—, —NHCO—, and —NHCO₂—. More preferred U_(n)R³ offormula III-a′ are those listed in Table 1 below.

Preferred compounds of formula III-a′ are those having one or more, morepreferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, or an optionally        substituted group selected from C₁₋₄ aliphatic, 3–6 membered        heterocyclic, or a 5–6 membered aryl or heteroaryl ring;    -   (b) T_(m)R¹ is hydrogen, N(R⁴)₂, OH, 3–6 membered carbocyclyl,        or an optionally substituted group selected from C₁₋₆ aliphatic        or a 5–6 membered aryl or heteroaryl ring; and    -   (c) R⁵ is an optionally substituted6-membered aryl, heteroaryl,        or carbocyclic ring.

More preferred compounds of formula III-a′ are those having one or more,more preferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is selected from hydrogen, methyl, ethyl, propyl,        cyclopropyl, cyclohexyl, isopropyl, —CH(CH₂OH) phenyl,        —CH(CH₂OH)ethyl, —CH(CH₂OH)₂, —CH(CH₂OH) isopropyl,        —CH(CH₂OH)CH₂cyclopropyl, or an optionally substituted phenyl or        benzyl group;    -   (b) T_(m)R¹ is selected from optionally substituted phenyl,        methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH,        OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and    -   (c) R⁵ is cyclohexyl or an optionally substituted phenyl or        pyridylring.

Preferred compounds of formula III-a are further selected from those offormula III-a°:

or a pharmaceutically acceptable derivative thereof.

Preferred R⁵ groups of formula III-a′ are R or OR⁷. Examples of suchgroups include OH, CH₂OH, or optionally substituted6-membered aryl,heteroaryl, and carbocyclic rings, such as phenyl, pyridyl, andcyclohexyl. Preferred R⁸ groups of formula III-a° are R and OR⁷, whereinR is an optionally substituted group selected from C₁₋₄ aliphatic, 3–6membered heterocyclic, or a 5–6 membered aryl or heteroaryl ring.Examples of such groups include phenyl, methyl, ethyl, OH, and CH₂OH.

Preferred T_(m)R¹ groups of formula III-a° are hydrogen, N(R⁴)₂, OH, 3–6membered carbocyclyl, or an optionally substituted group selected fromC₁₋₆ aliphatic or a 5–6 membered aryl or heteroaryl ring. When R¹ is anoptionally substituted phenyl or aliphatic group, preferred substituentson the phenyl or aliphatic group are R⁷, halo, nitro, alkoxy, and amino.Preferred T_(m)R¹ groups include methyl, ethyl, propyl, cyclopropyl,cyclohexyl, CH₂OCH₃, CH₂OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, and CH₂NHCH₃.More preferred T_(m)R¹ groups of formula III-a° are those listed inTable 1 below.

Preferred R³ groups of formula III-a° are hydrogen, carbocyclyl,—CH(R⁸)R, or an optionally substituted group selected from C₁₋₄aliphatic, 3–6 membered heterocyclic, or a 5–6 membered aryl orheteroaryl ring. Examples of such groups include methyl, ethyl, propyl,cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, andisopropyl. When R³ is optionally substituted phenyl, preferredsubstituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl,Obenzyl, Ophenyl, OCF₃, OH, SO₂NH₂, and methylene dioxy. When R³ is—CH(R⁸)R, examples of such groups are —CH(CH₂OH)phenyl, —CH(CH₂OH)ethyl,—CH(CH₂OH)₂, —CH(CH₂OH)isopropyl, and —CH(CH₂OH)CH₂cyclopropyl.Preferred U_(n) groups, when present, are —CH₂—, —O—, —NR⁷—, —NHCO—, and—NHCO₂—. More preferred U_(n)R³ groups of formula III-a° are thoselisted in Table 1 below.

Preferred compounds of formula III-a° are those having one or more, morepreferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, or an optionally        substituted group selected from C₁₋₄ aliphatic, 3–6 membered        heterocyclic, or a 5–6 membered aryl or heteroaryl ring;    -   (b) T_(m)R¹ is hydrogen, N(R⁴)₂, OH, 3–6 membered carbocyclyl,        or an optionally substituted group selected from C₁₋₆ aliphatic        or a 5–6 membered aryl or heteroaryl ring; and    -   (c) R⁵ is R or OR⁷, and R⁸ is R⁷ or OR⁷.

More preferred compounds of formula III-a° are those having one or more,more preferably more than one, and most preferably all, of the featuresselected from the group consisting of:

-   -   (a) R³ is selected from hydrogen, methyl, ethyl, propyl,        cyclopropyl, cyclohexyl, isopropyl, —CH(CH₂OH)phenyl,        —CH(CH₂OH)ethyl, —CH(CH₂OH)₂, —CH(CH₂OH)isopropyl,        —CH(CH₂OH)CH₂cyclopropyl, or an optionally substituted phenyl or        benzyl group;    -   (b) T_(m)R¹ is selected from optionally substituted phenyl,        methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH,        OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and    -   (c) R⁵ is OH, CH₂OH, phenyl, pyridyl, or cyclohexyl, and R⁸ is        methyl, ethyl, OH, or CH₂OH.

Preferred compounds of formula III-a are set Table 1 below. Morepreferred compounds in are those of formula III-a′ or III-a°.

TABLE 1^(A) Compounds of Formula III-a No. III-a- R³U_(n) T_(m)R¹ Q–R² 1H phenyl CON(Me)₂ 2 H 3-Cl-phenyl CO(pyrrolidin-1-yl) 3 H2-F-3-Cl-phenyl CO(pyrrolidin-1-yl) 4 H phenyl CONH(CH₂)₂pyridin-3-yl 5H phenyl CO(morpholin-4-yl) 6 H phenyl

7 H 3,4-(CH₃O)₂-phenyl

8 H 3,4-(CH₃O)₂-phenyl

9 H 3-Me-phenyl

10 H 2-F-3-Cl-phenyl

11 H 3-Me-phenyl

12 H phenyl

13 H phenyl

14 H phenyl

15 H phenyl

16 H 3,4-(CH₃O)₂-phenyl CO(morpholin-4-yl) 17 H 3,4-(CH₃O)₂-phenylCONH(CH₂)₂pyridin-3-yl 18 H 3-Me-phenyl CO(morphohn-4-yl) 19 H3-Me-phenyl CONH(CH₂)₂pyridin-3-yl 20 H 3-Cl-phenylCONH(CH₂)₂pyridin-3-yl 21 H 3-Cl-phenyl

22 H 3-Cl-phenyl

23 H 3-Cl-phenyl

24 H 3-Cl-phenyl

25 H 3-Cl-phenyl

26 H 2-F-3-Cl-phenyl CO(morpholin-4-yl) 27 H 3-Cl-phenylCO(4-OH-piperidin-1-yl) 28 H 3-Cl-phenyl

29 H phenyl CON(Me)CH₂Ph 30 H phenyl

31 H phenyl

32 H phenyl

33 H 3,4-(CH₃O)₂-phenyl CON(Me)CH₂Ph 34 H 3,4-(CH₃O)₂-phenyl

35 H 3,4-(CH₃O)₂-phenyl

36 H 3-Me-phenyl CON(Me)CH₂Ph 37 H 3-Me-phenyl

38 H 3-Me-phenyl

39 H 3-Me-phenyl

40 H 3-Cl-phenyl CON(Me)CH₂Ph 41 H 3-Cl-phenyl

42 H 2-F-3-Cl-phenyl CON(Me)CH₂Ph 43 H 3-Cl-phenyl

44 H 2-F-3-Cl-phenyl

45 H 3-Me-phenyl

46 H 3-Me-phenyl

47 H 3-Me-phenyl

48 H 3-Me-phenyl

49 H 2-F-3-Cl-phenyl

50 H 2-F-3-Cl-phenyl

51 H 2-F-3-Cl-phenyl

52 H 2-F-3-Cl-phenyl

53 H 2-F-3-Cl-phenyl

54 H 3-Cl-phenyl

55 H phenyl

56 H 3,4-(CH₃O)₂-phenyl

57 H 3,4-(CH₃O)₂-phenyl

58 H phenyl

59 H 3-Cl-phenyl CONH(CH₂)₂pyridin-3-yl 60 H 3-Me-phenyl

61 H 2-F-3-Cl-phenyl

62 H 2-F-3-Cl-phenyl

63 H 2-F-3-Cl-phenyl

64 H phenyl

65 H 3,4-(CH₃O)₂-phenyl

66 H 2-F-3-Cl-phenyl

67 H 3,4-(CH₃O)₂-phenyl

68 H 3-Cl-phenyl

69 H 3-Me-phenyl

70 H 3,4-(CH₃O)₂-phenyl

71 H phenyl CO(pyrrolidin-1-yl) 72 H 3-Cl-phenyl CO(morpholin-4-yl) 73 HMethyl CONHCH₂Ph 74 H Methyl CONHCH₂(3,4-F₂-phenyl) 75 H Methyl

76 H Methyl CONHCH₂(4-F-phenyl) 77 H Methyl CONHCH₂(3-Cl-phenyl) 78 HMethyl CONHCH₂(4-OMe-phenyl) 79 H Methyl CONHCH₂(3-Cl, 4-F-phenyl) 80 HMethyl

81 H Methyl

82 H Methyl

83 H Methyl

84 H NH₂

85 H NHCH₃

86 H NHC(O)CH₃

87 H NHC(O)NHCH₃

88 H OH

89 H CH₂NHCH₃

90 H CH₂OH

91 N-cyclohexyl NHC(O)NHCH₃

92 C(O)CH₃ NHC(O)NHCH₃

93 SO₂CH₃ OH

94 H SO₂CH₃

95 H CH₂OH

96 cyclohexyl CH₃

97 H 3,5-Cl₂-phenyl CONHCH₂pyridin-4-yl 98 phenyl 3,5-Cl₂-phenylCONHCH₂(3-CF₃-phenyl) 99 H 3,5-Cl₂-phenyl

100 H 3,5-Cl₂-phenyl

101 H 3,5-Cl₂-phenyl

102 H 3,5-Cl₂-phenyl

103 phenyl 3,5-Cl₂-phenyl

104 phenyl 3,5-Cl₂-phenyl

105 H 3-F, 5-CF₃-phenyl

106 H n-propyl CONH(CH₂)₂pyridin-3-yl 107 H methylCONH(CH₂)₂pyridin-3-yl 108 methyl methyl CONH(CH₂)₂pyridin-3-yl 109methyl H CONH(CH₂)₂pyridin-3-yl 110 ethyl methyl CONH(CH₂)₂N(CH₃)₂ 111pheny; methyl CONH(CH₂)₂CH₃ 112 phenyl methyl CONH(CH₂)₃phenyl 113 ethylmethyl

114 ethyl methyl

115 ethyl H CONHCH₂(2-CF₃-phenyl) 116 phenyl methyl

117 ethyl methyl

118 ethyl H

119 phenyl ethyl CONHCH(CH₃)₂ 120 phenyl methyl CONH(CH₂)₂NH₂ 121 H H

122 H H

123 ethyl methyl

124 ethyl methyl CONH(CH₂)₃phenyl 125 H ethyl

126 phenyl methyl

127 phenyl methyl

128 methyl methyl

129 methyl methyl

130 phenyl methyl

131 H methyl

132 (CH₂)₂N(Et)₂ methyl

133

methyl

134 methyl methyl

135 phenyl methyl

136 3-F-phenyl methyl

137 3-OMe-phenyl methyl

138 3-OH-phenyl methyl

139

methyl

140 4-SO₂NH₂-phenyl methyl

141 3-OBn-phenyl methyl

142

methyl

143 phenyl cyclohexyl

144 phenyl cyclopropyl

145 phenyl methyl

146 phenyl methyl

147 3-F-phenyl methyl

148 3-F-phenyl methyl

149 3-CF₃-phenyl methyl

150 CH₂phenyl methyl

151 3,4-Me₂-phenyl methyl

152 4-OBn-phenyl methyl

153 CH(CH₃)₂ methyl

154 CH₂CF₃ methyl

155

methyl

156 2-OMe-phenyl methyl

157 4-OCF₃-phenyl methyl

158 CH₂CH(CH₃)₂ methyl

159 CH₂cyclopropyl methyl

160 phenyl CH₂OCH₃

161 H CH₂OCH₃

162 cyclopropyl methyl

163 (CH₂)₂CH₃ methyl

164 phenyl CH₂OCH₃

165 phenyl CH₂OH

166

methyl

167 ethyl methyl

168 ethyl methyl

169 ethyl methyl

170 ethyl methyl

171 ethyl methyl

172 ethyl methyl

173 ethyl methyl

174

methyl

175 CH₂CH₂OH methyl

176

methyl

177

methyl

178

methyl

179

methyl

180 H H

181 H H

182 H H

183 H H

184 ethyl methyl

185 H H

186 H H

187 ethyl CH₂OCH₃

188 ethyl methyl

189 ethyl CH₂OH

190 ethyl methyl

191 ethyl methyl

192 ethyl methyl

193

methyl

194 2,3-Me₂-phenyl methyl

195 OCH₂CH₃ methyl

196

methyl

197 ethyl methyl

198 ethyl methyl

199 3-fluorophenyl methyl

200 2-Cl-phenyl methyl

201

methyl

202 cyclopropyl methyl

203 cyclopropyl methyl

204 cyclopropyl methyl

205 cyclopropyl methyl

206 O-Me methyl

207 O-isopropyl methyl

208 3-N(Me)₂-phenyl methyl

209 2-OH-phenyl methyl

210

methyl

211 2,3-Me₂-phenyl methyl

212 3-fluoro-phenyl methyl

213 acetyl methyl

214 2-Me-phenyl methyl

215 pyridin-3-yl methyl

216

methyl

217

methyl

218 NC(O)OEt methyl

219 CH₂pyridin-3-yl methyl

220

methyl

221 isoxazol-3-yl methyl

222

methyl

223 2-Me-phenyl methyl

224 2-Me-phenyl methyl

225 O(CH₂)₂OH methyl

226 N(Me)₂ methyl

227 2-CF₃-phenyl methyl

228

methyl

229

methyl

230

methyl

231 phenyl methyl

232

methyl

233

methyl

234

methyl

235

methyl

236

methyl

237

methyl

238 CN methyl

^(A)Compound names for the compounds of formula III-a shown above inTable 1 are set forth in Appendix A.

The above formula III-a compounds are those wherein Ring A is apyrimidine ring and Sp is a pyrrole ring. Inhibitors of formula Iwherein Ring A is a pyridine, pyrimidine, or triazine ring having theother Sp rings shown above are otherwise structurally similar to theformula III-a compounds and are represented by the following generalformulae II-b through II-j, III-b through III-j, and IV-b through IV-jshown below in Table 2;

TABLE 2 II-b

III-b

IV-b

II-b′

III-b′

IV-b′

II-c

III-c

IV-c

II-d

III-d

IV-d

II-e

III-e

IV-e

II-e′

III-e′

IV-e′

II-f

III-f

IV-f

II-g

III-g

IV-g

II-g′

III-g′

IV-g′

II-h

III-h

IV-h

II-h′

III-h′

IV-h′

II-i

III-i

IV-i

II-i′

III-i′

IV-i′

II-j

III-j

IV-j

II-j′

III-j′

IV-j′

The compounds shown above in Table 2 are structurally similar tocompounds of formula III-a where the pyrrole ring of formula III-a isreplaced by each of the following Sp rings: imidazole (b), pyrazole (c),triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole(h), furan (i), and thiophene (j). Accordingly, preferred QR², T_(m)R¹,and U_(n)R³ groups of the compounds shown above in Table 2 are asdescribed above for the formula III-a compounds.

In another embodiment, this invention provides a pharmaceuticallyacceptable composition comprising a compound shown above in Table 2 anda pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an ERK2-mediated disease, which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound shown above in Table 2 or apharmaceutically acceptable composition comprising said compound.

Another aspect of this invention relates to a method of inhibiting ERK2activity in a patient, which method comprises administering to thepatient a compound shown above in Table 2 or a pharmaceuticallyacceptable composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease, which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound shown above in Table 2 or apharmaceutically acceptable comprising said compound.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound shown above in Table 2 or a pharmaceuticallyacceptable composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease, which method comprisesadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound shown above in Table 2 or apharmaceutically acceptable comprising said compound.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound shown above in Table 2 ora pharmaceutically acceptable composition comprising said compound. Thismethod is especially useful for diabetic patients. Another methodrelates to inhibiting the production of hyperphosphorylated Tau protein,which is useful in halting or slowing the progression of Alzheimer'sdisease. Another method relates to inhibiting the phosphorylation ofβ-catenin, which is useful for treating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound shown above in Table 2 or a pharmaceuticallyacceptable composition comprising said compound.

Another method relates to inhibiting ERK2, Aurora-2, or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with a compound shown above in Table 2, or a pharmaceuticallyacceptable composition thereof, in an amount effective to inhibit ERK2,Aurora-2, or GSK-3.

Each of the aforementioned methods directed to the inhibition of ERK2,Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound shown above in Table 2,as described above.

The present compounds may be prepared in general by methods known tothose skilled in the art for analogous compounds, as illustrated by thegeneral Schemes I through XII and the synthetic examples shown below.

Scheme I above shows a general synthetic route that is used forpreparing the pyrrol-3-yl compounds of formula III-a of this inventionwhen R² is an optionally substituted phenyl group or aliphatic group. Instep (a), an optionally substituted acid chloride is combined withcompound 1, dichloromethane, and aluminum; trichloride to form compound2. In cases where benzoyl acid chlorides are used, a wide variety ofsubstituents on the phenyl ring are amenable to this reaction. Aliphaticacid chlorides are also used in many cases. Examples of suitable R²groups include, but are not limited to, those set forth in Table 1above.

The formation of amide 4 is achieved by treating compound 2 with anamine 3 in DMF. When amine 3 is a primary amine, the reaction proceedsat ambient temperature. When amine 3 is a secondary amine, the reactionis heated at 50° C. to achieve complete reaction and afford amide 4.

The formation of enamine 5 at step (c) is achieved by treating amide 4with (Me₂N)₂-CHOt-Bu at ambient temperature. Alternatively, the reactionto form enamine 5 at step (c) is also achieved by usingdimethylformamide-dimethylacetal (DMF-DMA). The reaction using DMF-DMAtypically requires elevated temperature to afford enamine 5 whereasusing (Me₂N)₂-OtBu has the advantage of proceeding at ambienttemperature to afford the enamine 5 in higher purity.

The formation of the pyrimidine compound 6 at step (d) is achieved bythe treatment of enamine 5 with guanidine at elevated temperature.Alternatively, use of a substituted guanidine results in an aminosubstituent as is illustrated by 8.

As an alternative method, in step (e) intermediate 5 may be cyclizedwith S-methyl thiourea to form the 2-thiomethylpyrimidine 7 which may inturn be oxidized with m-CPBA to the sulfone. The sulfonyl group may besubsequently displaced by an amine to generate the substitutedaminopyrimidine 8.

The compounds of formula III-a synthesized by this method, asexemplified in Table 1, were isolated by preparatory HPLC (reversephase, 10→90% MeCN in water over 15 minutes). The details of theconditions used for producing these compounds are set forth in theExamples.

Scheme II above shows a general method for preparing compounds 8 fromintermediate 5 and an N-substituted guanidine (9). Intermediate 5 may beprepared according to Scheme I steps (a), (b), and (c) shown above.Compound 5 is treated with N-substituted guanidine (9) and potassiumcarbonate in dimethylacetamide to form compound 8. This reaction isamenable to a variety of N-substituted guanidines to form compounds offormula III-a. The details of the conditions used for producing thesecompounds are set forth in the Examples.

Scheme III above shows a general synthetic route that may be used forpreparing the pyrrol-3-yl compounds of formula II-a of this invention.The conversion of intermediate 5 to product 8 may be achieved throughsteps (c), (d), and (e) according to the method described in JACS, 1957,pp 79.

Scheme IV above shows a general synthetic route that may be used forpreparing the imidazol-4-yl compounds of formula II-b of this invention.The conversion of intermediate 5 to product 8 may be achieved throughsteps (e), (f), and (g) according to the method described in JACS, 1957,pp 79.

Scheme V above shows a general synthetic route that may be used forpreparing the imidazol-2-yl compounds of formula II-b′ of thisinvention. The conversion of intermediate 5 to product 8 may be achievedthrough steps (e), (f), and (g) according to the method described inJACS, 1957, pp 79.

Scheme VI above shows a general synthetic route that may be used forpreparing the pyrazol-3-yl compounds of formula II-c of this invention.The conversion of intermediate 4 to product 7 may be achieved throughsteps (c), (d), and (e) according to the method described in JACS, 1957,pp 79.

Scheme VII above shows a general synthetic route that may be used forpreparing the oxazol-2-yl-compounds of formula II-e′ of this invention.The conversion of intermediate 5 to product 8 may be achieved throughsteps (c), (d), and (e) according to the method described in JACS, 1957,pp 79.

Scheme VIII above shows a general synthetic route that may be used forpreparing the thiazol-2-yl compounds of formula II-g′ of this invention.The conversion of intermediate 5 to product 8 may be achieved throughsteps (c), (d), and (e) according to the method described in JACS, 1957,pp 79.

Scheme IX above shows a general synthetic route that may be used forpreparing the thiazol-4-yl compounds of formula II-g of this invention.The conversion of intermediate 5 to product 8 may be achieved throughsteps (e), (f), and (g) according to the method described in JACS, 1957,pp 79.

Scheme X above shows a general synthetic route that is used forpreparing compounds of formula III-a where T_(m)R¹ is methoxymethyl orhydroxymethyl. In step (a), 3-methoxypropionyl chloride is combined withcompound 1, dichloromethane, and aluminum trichloride to form compound2.

The formation of amide 4 is achieved by treating compound 2 with anamine 3 in DMF. When amine 3 is a primary amine, the reaction proceedsat ambient temperature. When amine 3 was a secondary amine, the reactionis heated at 50° C. to achieve complete reaction and afford amide 4. Theformation of enamine 5 at step (c) is achieved by treating amide 4 with(Me₂N)₂-CHOt-Bu at ambient temperature.

The formation of the pyrimidine compound 6 at step (d) is achieved bythe treatment of enamine 5 with a guanidine at elevated temperature.Alternatively, use of a substituted guanidine results in an aminosubstituent.

To form compounds where T_(m)R¹ is hydroxymethyl, intermediate 6 may betreated with BBr₃ in dichloromethane to form compounds 7. One of skillin the art would recognize that the hydroxymethyl group of compound 7could be further derivatized to form a variety of compounds of formulaIII-a. The details of the conditions used for producing these compoundsare set forth in the Examples.

Scheme XI above shows a general method for preparing the triazinecompounds of formula IV-a. Step (a) is performed in the manner describedat Scheme I, step (b) above. Step (b) is performed in the mannerdescribed at Scheme I, step (a) above. The formation of the triazinering at step (c) may be performed according to the methods described byHirsch, J.; Petrakova, E.; Feather, M. S.; J Carbohydr Chem [JCACDM]1995, 14 (8), 1179–1186. Alternatively, step (c) may be performedaccording to the methods described by Siddiqui, A. U.; Satyanarayana,Y.; Rao, U. M.; Siddiqui, A. H.; J Chem Res, Synop [JRPSDC] 1995 (2),43.

Using the preparation of compound III-a-226 to illustrate, Scheme XIIabove shows a general synthetic route that is used for preparingcompounds of formula III-a where U_(n) is NR⁷. The formation of thepyrimidine compound III-a-226 at step (a) is achieved by the treatmentof enamine 5 with a guanidine 6 at elevated temperature. Alternatively,use of a substituted amino guanidine results in an hydrazynosubstituent.

In another embodiment, this invention provides a pharmaceuticallyacceptable composition comprising a compound of formula I′, I″, I°,III-a, III-a′, or III-a°, and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an ERK2-mediated disease, which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of compound of formula I′, I″, III-a, III-a′, orIII-a°, or a pharmaceutically acceptable composition comprising saidcompound.

Another aspect of this invention relates to a method of inhibiting ERK2activity in a patient, which method comprises administering to thepatient compound of formula I′, I″, I°, III-a, III-a′, or III-a°, or apharmaceutically acceptable composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease, which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound of formula I′, I″, I°, III-a, III-a′, orIII-a°, or a pharmaceutically acceptable composition comprising saidcompound.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula I′, I″, I°, III-a, III-a′, or III-a°,or a pharmaceutically acceptable composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease, which method comprisesadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound of formula I′, I″, I°, III-a, III-a′, orIII-a°, or a pharmaceutically acceptable composition comprising saidcompound.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula I′, I″, I°,III-a, III-a′, or III-a°, or a pharmaceutically acceptable compositioncomprising said compound. This method is especially useful for diabeticpatients. Another method relates to inhibiting the production ofhyperphosphorylated Tau protein, which is useful in halting or slowingthe progression of Alzheimer's disease. Another method relates toinhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula I′, I″, I°, III-a, III-a′, or III-a°, or apharmaceutically acceptable composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a CDK-2-mediated disease, which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound of formula I′, I″, I°, III-a, III-a′, orIII-a°, or a pharmaceutically acceptable composition comprising saidcompound.

The term “CDK-2-mediated condition” or “disease”, as used herein, meansany disease or other deleterious condition in which CDK-2 is known toplay a role. The term “CDK-2-mediated condition” or “disease” also meansthose diseases or conditions that are alleviated by treatment with aCDK-2 inhibitor. Such conditions include, without limitation, cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis. See Fischer, P. M. andLane, D. P., Current Medicinal Chemistry, 7; 1213–1245 (2000); Mani, S.,Wang, C., Wu, K., Francis, R. and Pestell,. R., Exp. Opin. Invest.Drugs, 9, 1849 (2000); Fry, D. W. and Garrett, M. D., Current Opinion inOncologic, Endocrine & Metabolic Investigational Drugs, 2, 40–59 (2000).

Another aspect of this invention relates to a method of treating orpreventing a Lck-mediated disease, which method comprises administeringto a patient in need of such a treatment a therapeutically effectiveamount of a compound of formula I′, I″, I°, III-a, III-a′, or III-a°; ora pharmaceutically acceptable composition comprising said compound.

The terms “Lck-mediated disease” or “Lck-mediated condition”, as usedherein, mean any disease state or other deleterious condition in whichLck is known to play a role. The terms “Lck-mediated disease” or“Lck-mediated condition” also mean those diseases or conditions that arealleviated by treatment with an Lck inhibitor. Lck-mediated diseases orconditions include, but are not limited to, autoimmune diseases such astransplant rejection, allergies, rheumatoid arthritis, and leukemia. Theassociation of Lck with various diseases has been described [Molina etal., Nature, 357, 161 (1992)].

Another aspect of this invention relates to a method of treating orpreventing an AKT3-mediated disease, which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound of formula I′, I″, I°, III-a, III-a′, orIII-a°, or a pharmaceutically acceptable composition comprising saidcompound.

The terms “AKT3-mediated disease” or “AKT3-mediated condition”, as usedherein, mean any disease state or other deleterious condition in whichAKT3 is known to play a role. The terms “AKT3-mediated disease” or“AKT3-mediated condition” also mean those diseases or conditions thatare alleviated by treatment with an AKT inhibitor. AKT3-mediateddiseases or conditions include, but are not limited to, proliferativedisorders, cancer, and neurodegenerative disorders. The association ofAKT3 with various diseases has been described [Zang, Q. Y., et al,Oncogene, 19 (2000)] and [Kazuhiko, N., et al, The Journal ofNeuroscience, 20 (2000)].

Another method relates to inhibiting ERK2, Aurora-2, CDK-2, Lck, AKT3,or GSK-3 activity in a biological sample, which method comprisescontacting the biological sample with a compound of formula I′, I″, I°,III-a, III-a′, or III-a°, or a pharmaceutically acceptable compositioncomprising said compound, in an amount effective to inhibit ERK2,Aurora-2, CDK-2, Lck, AKT3, or GSK-3.

Each of the aforementioned methods directed to the inhibition of ERK2,Aurora-2, CDK-2, Lck, AKT3, or GSK-3, or the treatment of a diseasealleviated thereby, is preferably carried out with a preferred compoundof formula I′, I″, I°, III-a, III-a′, or III-a°, as described above.More preferably, each of the aforementioned. methods is carried out witha preferred compound of formula I′, I″, I°, III-a′, or III-a°, and mostpreferably with a compound of formula I″, I°, III-a′, or III-a°.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

SYNTHETIC EXAMPLES

For compounds where the HPLC Method is designated as “A”, the followingmethod was utilized: a gradient of water:MeCN, 0.1% TFA (95:5→0:100) wasrun over 22 minutes at 1 mL/min and 214 nm. For compounds where the HPLCMethod is designated as “B”, the following method was utilized: agradient of water:MeCN, 0.1% TFA (90:10→0:100) was run over 8 minutes at1 mL/min and 214 nm. Each of methods A and B utilize the YMC ODS-AQ 55120A column with a size of 3.0×150 mm. As used herein, the term “R_(t)”refers to the retention time, in minutes, associated with the compoundusing the designated HPLC method.

Example 1

2,2,2-Trichloro-1-(4-phenyl acetyl-1H-pyrrol-2-yl)-ethanone (1): In adry flask, phenylacetyl chloride (1 equivalent) was combined with2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount ofdichloromethane (DCM) to dissolve the reactants. To the resultingsolution, at ambient temperature, was added aluminum trichloride (1equivalent). After 2 hours, the reaction mixture was applied directlyonto a silica gel column. Gradient elution with 10% ethyl acetate to 50%ethyl acetate in hexanes provided compound 1 in 60% yield. ¹H NMR(CDCl₃) δ 4.0 (s, 2H), 7.1–7.35 (m, 7H), 9.7 (br s, NH). HPLC usingmethod B provided R_(t) of 4.9 minutes. LC/MS (M+1) 330.2, (M−1) 328.1.

Example 2

2,2,2-Trichloro-1-(4-(3-Chlorophenyl) acetyl-1H-pyrrol-2-yl)-ethanone(2): In a dry flask, 3-chlorophenylacetyl chloride (1 equivalent) wascombined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimumamount of dichloromethane (DCM). To the resulting solution, at ambienttemperature, was added aluminum trichloride (1 equivalent). After 2hours, the reaction mixture was applied directly onto a silica gelcolumn. Gradient elution with 10% ethyl acetate to 50% ethyl acetate inhexanes provided compound 2. HPLC using method A provided R_(t) of 15minutes

Example 3

1-[5-(2,2,2-Trichloro-acetyl)-1H-pyrrol-3-yl)-propan-1-one (3): In a dryflask, 3-proprionyl chloride (1 equivalent) was combined with2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount ofdichloromethane (DCM). To the resulting solution, at ambienttemperature, was added aluminum trichloride (1 equivalent). After 2hours, the reaction mixture was applied directly onto a silica gelcolumn. Gradient elution with 10% ethyl acetate to 50% ethyl acetate inhexanes provided compound 3

Example 4

4-Phenylacetyl-1H-pyrrole-2-carboxylic acid benzylamide (4): To asolution of compound 1 (1 equivalent) in DMF, at ambient temperature,was added benzylamine (1.2 equivalents). After 24 hours, the solvent wasevaporated and the crude product 4 was used without purification. HPLCusing method B provided R_(t) of 3.8 minutes. FIA/MS (M+1) 319.3, (M−1)317.2.

Example 5

2-(3-Chlorophenyl)1-[5-(morpholine-4-carbonyl)-1H-pyrrol-3-yl]-ethanone(5): To a solution of compound 2 (1 equivalent) in DMF, at ambienttemperature, was added morpholine (1.2 equivalents). After 24 hours, thesolvent was evaporated and the crude product 5 was used withoutpurification. FIA/MS (M+1) 3.33.3, (M−1) 331.2. ¹H NMR was consistentwith expected structure.

Example 6

4-Propionyl-1H-pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide (6):To a solution of compound 3 (1 equivalent) in DMF, at ambienttemperature, was added 3,4-difluorobenzyl amine (1.2 equivalents). After24 hours, the solvent was evaporated and the crude product 6 was usedwithout purification.

Example 7

4-(3-Dimethylamino-2-phenyl-acryloyl)-1H-pyrrole-2-carboxylic acidbenzylamide (7): To a solution of compound 4 (1 equivalent) in THF, atambient temperature, was added (Me₂N)₂CHOt-Bu (3 equivalents). After 24hours, the solvent was evaporated and the crude product 7 was usedwithout purification. ¹H NMR (CDCl₃) δ 4.4 (s, 2H), 4.8 (s, NH), 6.8–7.4(m, 13H).

Example 8

2-(3-Chloro-phenyl)-3-dimethylamino-1-[5-(morpholine-4-carbonyl)-1H-pyrrol-3-yl]-propenone(8): To a solution of compound 5 (1 equivalent) in THF, at ambienttemperature, was added (Me₂N)₂CHOt-Bu (3 equivalents). After 24 hours,the solvent was evaporated and the crude product 8 was used withoutpurification. HPLC using method B provided R_(t) of 11.2 minutes.

Example 9

4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid3,4-difluoro-benzylamide (III-a-74): Step 1: To a solution of compound 6(1 equivalent) in THF, at ambient temperature, was added (Me₂N)₂CHOt-Bu(3 equivalents). After 24 hours, the solvent was evaporated and thecrude product was utilized without purification. Step 2: To a solutionof the compound formed above at Step 1 (1 equivalent) in ethanol, atambient temperature, was added guanidine (3 equivalents) and theresulting mixture heated at reflux. After 12 hours, the solvent wasevaporated and the crude product purified by preparatory HPLC (reversephase; 10–90% MeCN in water; 15 minutes) to afford the desired compoundIII-a-74. HPLC using method B provided R_(t) of 7.9 minutes. ¹H NMR wasconsistent with expected structure. FIA/MS Obs. M+1/M−1.

Example 10

{4-[2-Amino-5-(3-chlorophenyl)-pyrimidine-4-yl]-1H-pyrrol-2-yl}-morpholin-4-yl-methanone(III-a-72): To a solution of compound 8 (1 equivalent) in ethanol, atambient temperature, was added guanidine (3 equivalents) and theresulting mixture heated at reflux. After 12 hours, the solvent wasevaporated and the crude product purified by preparatory HPLC (reversephase; 10→90% MeCN in water; 15 minutes) to afford the desired compoundIII-a-72. HPLC using method B, R_(t)=7.9 minutes. ¹H NMR was consistentwith expected structure. FIA/MS Obs. (M+1) 384.4 amu.

Example 11

N-(2-Hydroxy-1-(S)-phenyl-ethyl)-guanidine•HCl: (S)-Phenylglycinol (0.38g, 2.7 mmol) and bis-Boc guanidine-(N)-triflate (0.9 g, 2.3 mmol) werecombined in methylene chloride (anhydrous, 5 mL) and stirred at ambienttemperature overnight. Completion of the reaction was verified by HPLC.The mixture was diluted with ethyl acetate, washed with 2M sodiumbisulfite, brine then dried over MgSO₄, filtered and concentrated invacuo. The bis-Boc guanidine intermediate was treated with 4NHCl/dioxane (5 mL) and stirred at room temperature until deprotectionwas complete (48 h) to afford the title compound.

Example 12

4-[2-(2-Hydroxy-1-(S)-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (III-a-155):4-(3-Dimethylamino-2-methyl-acryloyl)-1H-pyrrole-2-carboxylic acid(2-hydroxy-1-phenyl-ethyl)-amide (100 mg, 0.29 mmol) was combined withN-(S)-phenylglycinol guanidine•HCl (126 mg) and potassium carbonate (121mg) in N,N-dimethylacetamide (2 mL). The resulting suspension was heatedand stirred at 100° C. for 24 hours. The crude material was diluted withethyl acetate, washed with saturated NaHCO₃, brine, dried over MgSO4 andconcentrated in vacuo. Purification by prep HPLC (Gilson: Column CombiHTSB-C189 5 μM 21.2 mm×100 mm, eluent=0.1% TFA MeCN/H2O gradient) followedby preparative TLC (silica, 5% MeOH in CH₂Cl₂) afforded compoundIII-a-155 as a pale yellow solid (8.0 mg). HPLC Method B, R_(t)=4.76minutes; MS (FIA) 458.2 (M+1), 456.1 (M−1); ¹H NMR consistent withstructure.

Example 13

4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (III-a-162):4-(3-Dimethylamino-2-methyl-acryloyl)-1H-pyrrole-2-carboxylic acid(2-hydroxy-1-phenyl-ethyl)-amide (100 mg, 0.29 mmol) was combined withcyclopropyl guanidine•HCl (80 mg) and potassium carbonate (121 mg) inN,N-dimethylacetamide (2 mL). The resulting suspension was heated andstirred at 100° C. for 24 hours. The crude material was diluted withethyl acetate, washed with saturated NaHCO₃ and brine, dried over MgSO4then concentrated in vacuo. Purification by preparative TLC (silica, 1:1EtOAc:Hexanes) afforded III-a-162 as a yellow solid (7.8 mg). HPLCMethod B, R_(t)=4.29 minutes; LC/MS(m/z) 378.2 (M+1), 376.2 (M−1); ¹HNMR consistent with structure.

Example 14

3-Methoxy-1-[5-(2,2,2-trichloro-acetyl)-1H-pyrrol-3-yl]-propan-1-one: Toa solution of 2-trichloroacetyl pyrrole (1.0 equivalent, 4.67 g, 22mmol) in methylene chloride (5 mL) was added 3-methoxypropionyl chloride(1.0 equivalent, 22 mmol) then aluminium trichloride (1.0 equivalent,2.93 g, 22 mmol) was added in small portions. After 2.5 hours, the crudemixture was chromatographed on silica gel (MeOH 2% in DCM) to afford 3.0g of the Friedel-Craft product. ¹H NMR consistent with structure.

Example 15

4-(3-Methoxy-propionyl)-1H-pyrrole-2-carboxylic acid(2-hydroxy-1-(S)-phenyl-ethyl)-amide: To a solution of3-methoxy-1-[5-(2,2,2-trichloro-acetyl)-1H-pyrrol-3-yl]-propan-1-one(3.0 g, 10 mmol) in acetonitrile (50 mL), cooled to 0° C., was added(S)-(+)-phenyl glycinol (1.2 equivalent, 1.65 g, 12 mmol) and theresulting mixture stirred for 3 days at room temperature. The solventwas removed under reduced pressure and the residue purified bychromatography on silica gel (MeOH 5% in DCM) to afford 5.3 g of thetitle compound as a white solid. HPLC Method B, R_(t)=4.2 minutes;LC/MS(m/z) 317.03 (M+1), 315.00 (M−1); ¹H NMR consistent with structure.

Example 16

4-(3-Dimethylamino-2-methoxymethyl-acryloyl)-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide:4-(3-Methoxy-propionyl)-1H-pyrrole-2-carboxylic acid(2-hydroxy-1-(S)-phenyl-ethyl)-amide was treated with an excess ofBredereck's reagent in THF at room temperature to 50° C. for 3 days. Thesolvent was removed under reduced pressure and the concentrate was useddirectly in the next step. HPLC Method B, R_(t)=5.0 minutes “broadpeak”.

Example 17

4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (III-a-164):4-(3-Dimethylamino-2-methoxymethyl-acryloyl)-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (0.27 mmol) was combined withphenyl guanidine (73 mg) in N,N-dimethylacetamide (2 mL) and theresulting suspension was heated at 90° C. for 35 hours. The reactionmixture was diluted with ethyl acetate, washed with saturated NaHCO₃ andbrine, dried over MgSO₄ and concentrated in vacuo. The crude product waspurified by prep HPLC (Gilson: Column=CombiHT SB-C189 5 μM, 21.2 mm×100mm, eluent=0.1% TFA MeCN/H2O gradient) to afford III-a-164 as a yellowsolid (3.2 mg). LC/MS(m/z) 444.16 (M+1), 442.19 (M−1); HPLC Method B,R_(t)=5.16 minutes: ¹H NMR consistent with structure.

Example 18

4-(5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (III-a-165): To a solution ofIII-a-164 (15 mg, 0.03 mmol) in dichloromethane (2 mL), cooled to −78°C., was added BBr₃ (135 μL, 0.13 mmol). After 15 minutes the reactionwas allowed to warm to room temperature. After 45 minutes, the reactionwas quenched with a saturated solution of sodium carbonate and theresulting mixture was stirred for an additional 30 minutes beforeextraction with ethyl acetate. The organic layers were combined andwashed with brine then dried over sodium sulfate. The crude mixture waspurified by prep TLC (silica, 7% MeOH in CH₂Cl₂) to afford III-a-165 asa beige solid (1.6 mg). HPLC Method B, R_(t)=4.54 minutes; LC/MS (m/z)430.15 (M+1), 428.03 (M−1); ¹H NMR consistent with structure.

Example 19

4-(2-Amino-5-methoxymethyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid(2-hydroxy-1-phenyl-ethyl)-amide (III-a-161): The enamine formed aboveat Example 16 (0.27 mmol) was combined with guanidine•HCl (51 mg), andK₂CO₃ (100 mg) in N,N-dimethylacetamide (4 mL). The heterogenous mixturewas heated and stirred at 90° C. for 35 h. The crude material wasdiluted with ethyl acetate, washed with saturated NaHCO₃ and brine,dried (MgSO₄) and concentrated in vacuo. Purification by prep HPLC(Gilson: Column=CombiHT SB-C189 5 μM, 21:2 mm×100 mm, eluent=0.1% TFAMeCN/H₂O gradient) afforded III-a-161 as a yellow solid (2.0 mg).LC/MS(m/z) 368.12 (M+1), 366.15 (M−1), R_(t) (HPLC)=3.77 min, ¹H NMRconsistent with structure.

Example 20

4-(2-Mercapto-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid(2-hydroxy-1-(S)-phenyl-ethyl)-amide:4-(3-Dimethylamino-2-methoxymethyl-acryloyl)-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (17.6 mmol, 6.0 g) wascombined with thiourea (39 mmol, 3.0 g) and potassium carbonate (53mmol, 7.3 g) in ethanol (50 mL) and the resulting suspension was heatedat 90° C. for 24 hrs. The solvent was removed in vacuo and the resultingblack solid was diluted with water and the solid was removed byfiltration. The solid was washed with ethyl acetate twice and theaqueous solution was acidified to pH 5–6 with HCl (2N). The solid formedwas removed by filtration and the aqueous solution was then extractedtwice with ethyl acetate. The combined organic phases were dried oversodium sulfate. The solvent was removed under vacuum to afford the titlecompound as a brown solid (3.0 g, 48% yield). HPLC Method B, R_(t)=3.7minutes, ¹H NMR consistent with structure.

Example 21

4-(5-Methyl-2-propylsulfanyl-pyrimidin-4-yl)-4H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide: To a solution of4-(2-mercapto-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid(2-hydroxy-1-(S)-phenyl-ethyl)-amide (7.7 mmol, 2.74 mmol) in aqueousammonia (15%) was added at room temperature n-propyliodide (11.6 mmol,1.1 mL). The solution was stirred overnight at room temperature. Theresulting solid was collected by filtration and used directly for thenext step. ¹H NMR consistent with the structure.

Example 22

4-[5-Methyl-2-(propane-1-sulfonyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide: The thiopropyl compound (7.7mmol, 3.05 g) prepared at Example 21 above was dissolved in 120 mL ofethanol. To this solution, maintained at room temperature, was addedm-CPBA (70% w/w %, 23.1 mmol, 4.0 g). The solution was stirred for anadditional. 4 hours at room temperature. The solvent was removed invacuo and the residue dissolved in ethyl acetate, then washed 4 timeswith a solution of sodium hydroxide (1N). The organic phase was driedover sodium sulfate and concentrated in vacuo to afford the titlecompound as a white solid (1.7 g, 51% yield for 2 steps) HPLC Method B,R_(t)=5.4 minutes. ¹H NMR consistent with the structure.

Example 23

4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboylic acid(2-hydroxy-1-(S)-phenyl-ethyl)-amide: To a solution of4-[5-methyl-2-(propane-1-sulfonyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (47 μmol, 20 mg) in DMSO (1mL) was added ethylamine (0.5 mmol, 150 μL). The mixture was heated at130° C. for 24 hours to afford the title compound. LC/MS(m/z) 366.2(M+1); HPLC Method B, R_(t)=4.2 minutes; ¹H NMR consistent with thestructure.

Example 24

4-[2-(N′,N′-Dimethyl-hydrazino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (III-a-226): To a solution of4-(3-dimethylamino-2-methoxymethyl-acryloyl)-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (0.15 mmol, 50 mg) in DMA (2mL) was added dimethyl-N,N-aminoguanidine•2HCl (0.17 mmol, 30 mg) andpotassium carbonate (0.36 mmol, 50 mg). The reaction Mixture was stirredfor 48 hrs at 100° C. The solvent was removed by hi-vacuum “GeneVac” andthe residue purified by preparative HPLC (Gilson: Column=CombiHT SB-C1895 μM 21.2 mm×100 mm, eluent=0.1% TFA MeCN/H2O gradient) followed bypreparative TLC (silica, 5% MeOH in CH₂Cl₂) “double elutions” affordedcompound III-a-226 as a pale yellow solid (1.3 mg). HPLC Method B,R_(t)=4.03 min.; LC/MS (m/z) 381.1 (M+1), 379.1 (M−1); ¹H NMR consistentwith structure.

Example 25

Ethanolguanidine: Ethanolamine hydrochloride (200 mg, 2 mmol) was addedto a mixture of N, N′-di-boc -N″-triflylguanidine (800 mg, 2 mmol) andTEA (0.28 mL, 2 mmol) in dichloromethane (10 mL). The mixture wasstirred overnight then diluted with EtOAc, washed with sodium bisulfate(2M), saturated sodium bicarbonate, dried over NaSO₄ and concentrated invacuo. The crude residue was purified by flash column chromatographyeluting with 20% CH₂Cl₂/hexane to afford a white solid (0.56 g, 92%).).¹H NMR (CDCl₃): δ 4.18 (q, 2H), 1.60 (d, 18H), 1.37 (t, 3H). To thisbis-Boc guanidine was added 4M HCl/dioxane (5 mL). The mixture wasstirred for 24 h and then concentrated to afford the title compound(0.26 g). ¹H NMR (MeOD): δ 3.92 (q, 2H), 1.27 (t, 3H). MS (M+1) 104.

Example 26

4-(2-Ethanolamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid(2-hydroxy-1-(s)-phenyl-ethyl)-amide (III-a-195): To a mixture of4-(3-dimethylamino-2-methyl-acryloyl)-1H-pyrrole-2-carboxylic acid(2-hydroxymethyl-1-(S)-phenyl-ethyl) amide (0.1 mmol) and K₂CO₃ (55 mg,0.4 mmol) in DMF (1 mL) was added ethanolguanidine hydrogen chloride(0.2 mmol). The resulting suspension was stirred for 6 hours at 90° C.The reaction mixture was filtered and the filtrate concentrated invacuo. The crude residue was purified by preparative HPLC (Gilson:Column=CombiHT SB-C189 5 μM 21.2 mm×100 mm, eluent=0.1% TFA MeCN/H2Ogradient) to afford compound III-a-195 as yellow oil (21 mg). HPLC(method B) R_(t)=4.08 min; MS (M+1) 382.1.

Example 27

Ethyl carbamate guanidine: Ethylcarbazate (208 mg, 2 mmol) was added toa solution of N′N′-di-boc N″-triflylguanidine (800 mg, 2 mmol) indichloromethane (10 mL). The mixture was stirred for overnight thendiluted with EtOAc, washed with sodium bisulfat (2M), saturated sodiumbicarbonate, dried over anhydrous NaSO₄ and concentrated in vacuo. Thecrude residue was purified by flash column chromatography eluting with30% EtOAc/hexane to afford a white solid (0.55 g). To this bis-bocguanidine was added 4M HCl/Dioxane (5 mL). The mixture was stirred for24 hours and then concentrated to afford the title compound. ¹H NMR(MeOD): δ 3.4.18 (d, 2H), 3.26 (s, 1H), 1.28 (t, 3H). MS (M+1) 134.

Example 28

4-(2-Ethyl carbamate-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylicacid (2-hydroxy-1-(s)-phenyl-ethyl)-amide (III-a-218): To a mixture of4-(3-dimethylamino-2-methyl-acryloyl)-1H-pyrrole-2-carboxylic acid(2-hydroxymethyl-1-(S)-phenyl-ethyl) amide (0.1 mmol) and K₂CO₃ (55 mg,0.4 mmol) in DMF (1 mL) was added ethyl carbamate guanidine hydrogenchloride (0.2 mmol). The resulting suspension was stirred for 6 hours at90° C. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The crude residue was purified by preparativeHPLC (Gilson: Column=CombiHT SB-C189 5 μM 21.2 mm×100 mm, eluent=0.1%TFA MeCN/H2O gradient) to afford compound III-a-218 as a yellow oil (10mg). HPLC (method B) R_(t)=4.03; MS (M+1) 425.1. ¹H NMR (MeOD) 8.08 (s,1H); 7.87 (s, 1H); 7.7 (s, 1H), 7.24–7.5 (m, 5H); 5.15 (t, 1H), 4.2 (m,2H), 3.85 (m, 2H); 2.5 (s, 3H).

Example 29

We have prepared other compounds of formula III-a by methodssubstantially similar to those described in the above Examples 1–28 andthose illustrated in Schemes I–XII. The characterization data for thesecompounds is summarized in Table 3 below and includes LC/MS, HPLC, and¹H NMR data.

Where applicable, ¹H NMR data is summarized in Table 3 below wherein “Y”designates ¹H NMR data is available and was found to be consistant withstructure. Compound numbers correspond to the compound numbers listed inTable 1.

TABLE 3 Characterization Data for Selected Compounds Compound No III-a-M + 1 M − 1 HPLC Method R_(t) (min) ¹H NMR 122 352.17 — — — — 136 432.2429.8 B 5.53 — 137 444.3 442.3 B 5.00 — 138 430.2 428.3 B 4.47 Y 139458.3 456.3 B 4.72 — 140 493.3 491.3 B 4.45 — 141 520.2 518.2 B 5.98 —142 436.2 — B 4.0 — 144 440.17 — A 10.1 Y 145 446.2 444.1 B 5.45 — 146482.2 — B 5.69 — 147 464.2 — B 5.87 — 148 500.1 — B 6.12 — 149 482.2480.4 B 6.11 — 150 428.2 426.2 B 5.13 — 153 380.2 378.2 B 4.63 Y 154420.1 418.1 B 4.74 Y 155 458.2 456.1 B 4.76 Y 156 441.13 — B 5.14 — 157498.2 — B 6.00 — 159 392.2 390.1 B 4.75 Y 162 378.2 376.2 B 4.29 Y 163380.2 378.0 B 4.65 Y 180 338.15 — B 3.8 — 181 396.22 — B 3.9 — 182382.18 — B 4.1 — 183 352.17 — — — — 188 367.2 — B 2.86 Y 190 453.1 — B5.86 Y 191 384.1 — B 4.46 Y 192 384.1 — B 4.41 Y 214 428.1 — B 4.9 — 215415.1 — B 4.3 Y 216 422.1 — B 4.43 Y 217 422.1 — B 4.44 — 219 429.3 — B3.64 Y 221 405.19 — B 4.5 — 227 482.4 — B 5.5 — 229 419.03 — B 4.29 Y230 510.4 — B 5.19 — 231 432.3 — B 5.23 Y

Biological Testing

The activity of the present compounds as protein kinase inhibitors maybe assayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the phosphorylation activityor ATPase activity of the activated protein kinase. Alternate in vitroassays quantitate the ability of the inhibitor to bind to the proteinkinase. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor protein kinasecomplex and determining the amount of radiolabel bound. Alternatively,inhibitor binding may be determined by running a competition experimentwhere new inhibitors are incubated with the protein kinase bound toknown radioligands. The details of the conditions used for performingthese assays are set forth in Examples 30 through 37.

Example 30 ERK Inhibition Assay

Compounds were assayed for the inhibition of ERK2 by aspectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7,2249). In this assay, a fixed concentration of activated ERK2 (10 nM)was incubated with various concentrations of the compound in DMSO (2.5%)for 10 min. at 30° C. in 0.1 M HEPES buffer, pH 7.5, containing 10 mMMgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM erktide peptide. Thereaction was initiated by the addition of 65 μM ATP. The rate ofdecrease of absorbance at 340 nM was monitored. The IC₅₀ was evaluatedfrom the rate data as a function of inhibitor concentration.

Table 4 shows the results of the activity of selected compounds of thisinvention in the ERK2 inhibition assay. The compound numbers correspondto the compound numbers in Table 1. Compounds having an activitydesignated as “A” provided a percent inhibition less than or equal to33%; compounds having an activity designated as “B” provided a percentinhibition of between 24% and 66%; and compounds having an activitydesignated as “C” provided a provided a percent inhibition of between67% and 100%. Compounds having an activity designated as “ID” provided aK_(i) of less than 0.1 micromolar; compounds having an activitydesignated as “E” provided a K_(i) of between 0.1 and 1.0 micromolar;and compounds having an activity designated as “F” provided a K_(i) ofgreater than 1.0 micromolar.

TABLE 4 ERK2 Inhibitory Activity of Selected Compounds No. No. No.III-a- Activity III-a- Activity III-a- Activity 2 B 3 A 4 A 5 A 6 A 7 A8 A 9 A 10 A 11 A 12 B 13 A 14 B 15 A 16 A 17 A 18 A 19 A 20 A 21 B 22 A23 C 24 A 25 A 26 A 27 A 28 A 29 C 30 A 31 A 32 A 33 A 34 B 35 B 36 B 37C 39 C 40 C 41 A 42 C 43 A 44 C 45 B 46 A 47 C 48 B 49 A 50 A 51 A 52 A53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 C 63 A 64 A 65 A 66 A 67A 68 A 69 A 70 A 71 A 72 B 100 A 101 A 102 A 103 F 104 A 105 E 107 F 111D 112 D 114 F 117 D 120 E 121 A 122 C 123 A 124 C 125 A 131 A 132 F 133F 134 D 135 C 139 D 140 D 141 D 142 D 144 E 145 D 147 D 148 D 149 D 150D 151 D 152 D 153 D 154 D 155 D 157 D 158 D 159 D 160 E 161 E 162 D 163D 166 E 168 F 169 E 170 F 171 F 172 F 173 E 174 D 175 D 176 D 177 D 178D 179 D 180 F 184 E 188 E 189 D 190 E 191 D 192 E 193 D 194 D 195 D 196D 197 F 198 D 199 D 200 D 201 D 202 D 203 D 204 D 205 D 206 D 207 D 208D 209 D 210 D 211 D 212 D 213 D 214 D 215 D 216 D 217 D 218 E 219 D 220D 221 D 222 D 223 D 224 D 225 D 226 D 227 D 229 E 230 D 231 D 232 D 233D 234 D 235 D 236 D 237 D 238 D — —

Example 31 ERK2 Inhibition: Cell Proliferation Assay

Compounds may be assayed for the inhibition of ERK2 by a cellproliferation assay. In this assay, a complete media is prepared byadding 10% fetal bovine serum and penicillin/streptomycin solution toRPMI 1640 medium (JRH Biosciences). Colon cancer cells (HT-29 cell line)are added to each of 84-wells of a 96 well plate at a seeding density of10,000 cells/well/150 μL. The cells are allowed to attach to the plateby incubating at 37° C. for 2 hours. A solution of test compound isprepared in complete media by serial dilution to obtain the followingconcentrations: 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, and 0.08 μM.The test compound solution (50 μL) is added to each of 72cell-containing wells. To the 12 remaining cell-containing wells, onlycomplete media (200 μL) is added to form a control group in order tomeasure maximal proliferation. To the remaining 12 empty wells, completemedia is added to form a vehicle control group in order to measurebackground. The plates are incubated at 37° C. for 3 days. A stocksolution of ³H-thymidine (1 mCi/mL, New England Nuclear, Boston, Mass.)is diluted to 20 μCi/mL in RPMI medium then 20 μL of this solution isadded to each well. The plates are further incubated at 37° C. for 8hours then harvested and analyzed for ³H-thymidine uptake using a liquidscintillation counter.

Compounds III-a-116, III-a-139, and III-a-136 were each shown to have anIC₅₀ of less than 0.1 μM.

Example 32 ERK1 Inhibition Assay

Compounds were assayed for the inhibition of ERK1 by aspectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7,2249). In this assay, a fixed concentration of activated ERK1 (20 nM)was incubated with various concentrations of the compound in DMSO (2.0%)for 10 min. at 30° C. in 0.1 M HEPES buffer, pH 7.6, containing 10 mMMgCl₂, 2.5 mM-phosphoenolpyruvate, 200 μM NADH, 30 μg/mL pyruvatekinase, 10 μg/mL lactate dehydrogenase, and 150 μM erktide peptide. Thereaction was initiated by the addition of 140 μM ATP (20 μL). The rateof decrease of absorbance at 340 nM was monitored. The K_(i) wasevaluated from the rate data as a function of inhibitor concentration.

Examples of compounds that were found to inhibit ERK1 with an activityof less than 0.1 μM include III-a-202, III-a-204, and III-a-205.

Example 33 GSK-3 Inhibition Assay

Compounds were screened for their ability to inhibit GSK-3β (AA 1–420)activity using a standard coupled enzyme system (Fox et al. (1998)Protein Sci. 7, 2249). Reactions were carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH,1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were20 μM ATP (Sigma Chemicals, St Louis, Mo.) and 300 μM peptide(HSSPHQS(PO₃H₂)EDEEE, American Peptide, Sunnyvale, Calif.). Reactionswere carried out at 30° C. and 20 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. The assay stock buffer'solution (175 μl) was incubated in a 96well plate with 5 μl of the test compound of interest at finalconcentrations spanning 0.002 μM to 30 μM at 30° C. for 10 min.Typically, a 12 point titration was conducted by preparing serialdilutions (from 10 mM compound stocks) with DMSO of the test compoundsin daughter plates. The reaction was initiated by the addition of 20 μlof ATP (final concentration 20 μM). Rates of reaction were obtainedusing a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.)over 10 min at 30° C. The K_(i) values were determined from the ratedata as a function of inhibitor concentration.

Table 5 shows the results of the activity of selected compounds of thisinvention in the GSK3 inhibition assay. The compound numbers correspondto the compound numbers in Table 1. Compounds having an activitydesignated as “A” provided a K_(i) of less than 0.1 micromolar;compounds having an activity designated as “B” provided a K_(i) ofbetween 0.1 and 1.0 micromolar; and compounds having an activitydesignated as “C” provided a K_(i) of greater than 1.0 micromolar.

TABLE 5 GSK3 Inhibitory Activity of Selected Compounds No. No. No. IIIa-Activity IIIa- Activity IIIa- Activity 116 A 117 A 134 C 136 A 137 A 138A 139 A 140 A 141 A 142 A 144 C 145 A 146 B 147 A 148 A 149 A 150 B 151A 152 A 153 A 154 A 155 B 156 B 157 A 158 A 159 A 162 A 166 C 172 C 173C 174 A 175 B 176 A 177 B 178 B 179 A 181 C 184 C 187 C 188 C 189 C 190B 191 B 193 B 194 A 196 C 198 C 199 A 200 C 201 B 202 C 203 B 205 B 206A 207 B 208 A 209 A 210 C 211 B 212 A 213 B 214 B 215 A 216 A 217 A 222B 223 A 224 A 225 A 227 C 228 A 230 B 231 A 232 B 233 C

Example 34 Aurora-2 Inhibition Assay

Compounds were screened in the following manner for their ability toinhibit Aurora-2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mMMgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and800 μM peptide (LRRASLG, American Peptide, Sunnyvale, Calif.) was addeda DMSO solution of a compound of the present invention to a finalconcentration of 30 μM. The resulting mixture was incubated at 30° C.for 10 min. The reaction was initiated by the addition of 10 μL ofAurora-2 stock solution to give a final concentration of 70 nM in theassay. The rates of reaction were obtained by monitoring absorbance at340 nm over a 5 minute read time at 30° C. using a BioRad Ultramarkplate reader (Hercules, Calif.). The K_(i) values were determined fromthe rate data as a function of inhibitor concentration. Examples ofcompounds that were found to inhibit Aurora-2 include III-a-116,III-a-117, III-a-136, III-a-138, III-a-139, III-a-140, and III-a-141.

Example 35 CDK-2 Inhibition Assay

Compounds were screened in the following manner for their ability toinhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mMMgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and100 μM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, Calif.)was added a DMSO solution of a compound of the present invention to afinal concentration of 30 μM. The resulting mixture was incubated at3020 C. for 10 min.

The reaction was initiated by the addition of 10 μL of CDK-2/Cyclin Astock solution to give a final concentration of 25 nM in the assay. Therates of reaction were obtained by monitoring absorbance at 340 nm overa 5-minute read time at 3020 C. using a BioRad Ultramark plate reader(Hercules, Calif.). The K_(i) values were determined from the rate dataas a function of inhibitor concentration.

The following compounds were shown to have K_(i) values than 0.1 μM forCDK-2: III-a-116, III-a-142, III-a-149, and III-a-152.

The following compounds were shown to have K_(i) values between 0.1 μMand 1 M for CDK-2: III-a-146, III-a-148, III-a-150, III-a-155,III-a-162, and III-a-174.

The following compounds were shown to have K_(i) values between 1.0 and20.0 μM for CDK-2: III-a-117, III-a-156, and III-a-159.

Example 36 LCK Inhibition Assay

The compounds were evaluated as inhibitors of human Lck kinase usingeither a radioactivity-based assay or spectrophotometric assay.

Lck Inhibition Assay A: Radioactivity-based Assay

The compounds were assayed as inhibitors of full length bovine thymusLck kinase (from Upstate Biotechnology, cat. no. 14-106) expressed andpurified from baculo viral cells. Lck kinase activity was monitored byfollowing the incorporation of ³³P from ATP into the tyrosine of arandom poly Glu-Tyr polymer substrate of composition, Glu:Tyr=4:1(Sigma, cat. no. P-0275). The following were the final concentrations ofthe assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl₂, 2 mM DTT, 0.25mg/ml BSA, 10 μM ATP (1–2 μCi ³³P-ATP per reaction), 5 mg/ml polyGlu-Tyr, and 1–2 units of recombinant human Src kinase. In a typicalassay, all the reaction components with the exception of ATP werepre-mixed and aliquoted into assay plate wells. Inhibitors dissolved inDMSO were added to the wells to give a final DMSO concentration of 2.5%.The assay plate was incubated at 30° C. for 10 min before initiating thereaction with ³³P-ATP. After 20 min of reaction, the reactions werequenched with 150 μl of 10% trichloroacetic acid (TCA) containing 20 mMNa₃PO₄. The quenched samples were then transferred to a 96-well filterplate (Whatman, UNI-Filter GF/F Glass Fiber Filter, cat no. 7700-3310)installed on a filter plate vacuum manifold. Filter plates were washedfour times with 10% TCA containing 20 mM Na₃PO₄ and then 4 times withmethanol. 200 μl of scintillation fluid was then added to each well. Theplates were sealed and the amount of radioactivity associated with thefilters was quantified on a TopCount scintillation counter. Theradioactivity incorporated was plotted as a function of the inhibitorconcentration. The data was fitted to a competitive inhibition kineticsmodel to get the K_(i) for the compound.

Lck Inhibition Assay B: Spectrophotometric Assay

The ADP produced from ATP by the human recombinant Lck kinase-catalyzedphosphorylation of poly Glu-Tyr substrate was quanitified using acoupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In thisassay one molecule of NADH is oxidised to NAD for every molecule of ADPproduced in the kinase reaction. The disappearance of NADH can beconveniently followed at 340 nm.

The following were the final concentrations of the assay components:0.025 M HEPES, pH 7.6, 10 mM MgCl₂, 2 mM DTT, 5 mg/ml poly Glu-Tyr, and50 nM of recombinant human Lck kinase. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,200 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

In a typical assay, all the reaction components with the exception ofATP were pre-mixed and aliquoted into assay plate wells. Inhibitorsdissolved in DMSO were added to the wells to give a final DMSO.concentration of 2.5%. The assay plate was incubated at 30° C. for 10min before initiating the reaction with 150 μM ATP. The absorbancechange at 340 nm with time, the rate of the reaction, was monitored on amolecular devices plate reader. The data of rate as a function of theinhibitor concentration was fitted to competitive inhibition kineticsmodel to get the K_(i) for the compound.

The following compounds were shown to have K_(i) values than 1 μM forLck: III-a-170, III-a-171, III-a-172, III-a-173, III-a-181, andIII-a-203.

The following compounds were shown to have K_(i) values between 1.0 and20.0 μM for Lck: III-a-204, III-a-205, III-a-206, and III-a-207.

Example 37 AKT3 Inhibition Assay

Compounds were screened for their ability to inhibit AKT3 using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mMMgCl₂, 25 mM NaCl , 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay were 170 μM ATP (Sigma Chemicals) and 200 μMpeptide (RPRAATF, American Peptide, Sunnyvale, Calif.). Assays werecarried out at 30° C. and 45 nM AKT3. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ML pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of AKT3, DTT, and the testcompound of interest. 56 μl of the stock solution was placed in a 384well plate followed by addition of 1 μl of 2 mM DMSO stock containingthe test compound (final compound concentration 30 μM). The plate waspreincubated for about 10 minutes at 30° C. and the reaction initiatedby addition of 10 μl of enzyme (final concentration 45 nM) and 1 mM DTT.Rates of reaction were obtained using a BioRad Ultramark plate reader(Hercules, Calif.) over a 5 minute read time at 30° C. Compounds showinggreater than 50% inhibition versus standard wells containing the assaymixture and DMSO without test compound were titrated to determine IC₅₀values.

Selected compounds of this invention that inhibit AKT3 include:III-a-238.

While we have presented a number of embodiments of this invention, it isapparent that our basic construction can be altered to provide otherembodiments which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments which have been represented by way of example.

Appendix A: Names of Table 1 Compound Numbers III-a-

-   1: 4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    dimethylamide;-   2:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-pyrrolidin-1-yl-methanone;-   3:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-pyrrolidin-1-yl-methanone;-   4: 4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (2-pyridin-3-yl-ethyl)-amide;-   5:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;-   6:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-[1,4′]bipiperidinyl-1′-yl-methanone;-   7:    {4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(3-hydroxy-piperidin-1-yl)-methanone;-   8:    {4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[1,4′]bipiperidinyl-1′-yl-methanone;-   9:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-[1,4′]bipiperidinyl-1′-yl-methanone;-   10:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[1,4′]bipiperidinyl-1′-yl-methanone;-   11:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(4-hydroxy-piperidin-1-yl)-methanone;-   12:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   13:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(4-phenyl-piperazin-1-yl)-methanone;-   14:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;-   15:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(4-pyridin-2-yl-piperazin-1-yl)-methanone;-   16:    {4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-morpholin-4-yl-methanone;-   17:    4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-pyridin-3-yl-ethyl)-amide;-   18:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;-   19: 4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-pyridin-3-yl-ethyl)-amide;-   20:    4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-pyridin-3-yl-ethyl)-amide;-   21:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   22:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-phenyl-piperazin-1-yl)-methanone;-   23:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;-   24:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;-   25:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-1-yl)-methanone;-   26:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-morpholin-4-yl-methanone;-   27:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-hydroxy-piperidin-1-yl)-methanone;-   28:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[1,4′]bipiperidinyl-1′-yl-methanone;-   29: 4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    benzyl-methyl-amide;-   30:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;-   31:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(2-hydroxymethyl-piperidin-1-yl)-methanone;-   32:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;-   33:    4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid benzyl-methyl-amide;-   34:    {4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;-   35:    {4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;-   36: 4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid benzyl-methyl-amide;-   37:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(4-phenyl-piperazin-1-yl)-methanone;-   38:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(4-methyl-[1,4]diazepan-1-yl)-methanone;-   39:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;-   40:    4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid benzyl-methyl-amide;-   41:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)-methanone;-   42:    4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid benzyl-methyl-amide;-   43:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[2-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone;-   44:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-phenyl-piperazin-1-yl)-methanone;-   45:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   46:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(3-hydroxy-piperidin-1-yl)-methanone;-   47:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;-   48:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;-   49:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   50:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;-   51:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)-methanone;-   52:    1-(4-{4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carbonyl}-piperazin-1-yl)-ethanone;-   53:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;-   54:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(3-hydroxy-piperidin-1-yl)-methanone;-   55:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(4-methyl-[1,4]diazepan-1-yl)-methanone;-   56:    1-(4-{4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carbonyl}-piperazin-1-yl)-ethanone;-   57:    {4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-methyl-[1,4]diazepan-1-yl)-methanone;-   58:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(3-hydroxy-piperidin-1-yl)-methanone;-   59:    4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid methyl-(2-pyridin-2-yl-ethyl)-amide;-   60:    [4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-[2-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone;-   61:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[2-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone;-   62:    4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-methyl-2-phenyl-ethyl)-methyl-amide;-   63:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-1-yl)-methanone;-   64:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-(4-hydroxy-piperidin-1-yl)-methanone;-   65:    {4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-hydroxy-piperidin-1-yl)-methanone;-   66:    {4-[2-Amino-5-(3-chloro-2-fluoro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-hydroxy-piperidin-1-yl)-methanone;-   67:    {4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-1-yl)-methanone;-   68:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone;-   69:    1-{4-[4-(2-Amino-5-m-tolyl-pyrimidin-4-yl)-1H-pyrrole-2-carbonyl]-piperazin-1-yl}-ethanone;-   70:    {4-[2-Amino-5-(3,4-dimethoxy-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   71:    [4-(2-Amino-5-phenyl-pyrimidin-4-yl)-1H-pyrrol-2-yl]-pyrrolidin-1-yl-methanone;-   72:    {4-[2-Amino-5-(3-chloro-phenyl)-pyrimidin-4-yl]-1H-pyrrol-2-yl}-morpholin-4-yl-methanone;-   73: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    benzylamide;-   74: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    3,4-difluoro-benzylamide;-   75: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (2-hydroxy-1-phenyl-ethyl)-amide;-   76: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    4-fluoro-benzylamide;-   77: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    3-chloro-benzylamide;-   78: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    4-methoxy-benzylamide;-   79: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    3-chloro-4-fluoro-benzylamide;-   80: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (tetrahydro-furan-2-ylmethyl)-amide;-   81: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (tetrahydro-furan-2-ylmethyl)-amide;-   82: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (3-hydroxy-1-phenyl-propyl)-amide;-   83: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (3-hydroxy-1-phenyl-propyl)-amide;-   84: 4-(2,5-Diamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    3-chloro-4-fluoro-benzylamide;-   85: 4-(2-Amino-5-methylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid 3-chloro-4-fluoro-benzylamide;-   86: 4-(5-Acetylamino-2-amino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid 3-chloro-4-fluoro-benzylamide;-   87:    4-[2-Amino-5-(3-methyl-ureido)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid 3-chloro-4-fluoro-benzylamide;-   88: 4-(2-Amino-5-hydroxy-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid 3-chloro-4-fluoro-benzylamide;-   89:    4-(2-Amino-5-methylaminomethyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid 3-chloro-4-fluoro-benzylamide;-   90:    4-(2-Amino-5-hydroxymethyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid 3-chloro-4-fluoro-benzylamide;-   91:    4-[2-Cyclohexylamino-5-(3-methyl-ureido)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid 3-chloro-4-fluoro-benzylamide;-   92:    4-[2-Acetylamino-5-(3-methyl-ureido)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid 3-chloro-4-fluoro-benzylamide;-   93:    4-(5-Hydroxy-2-methanesulfonylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid 3-chloro-4-fluoro-benzylamide;-   94:    4-(2-Amino-5-methanesulfonyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid 3-chloro-4-fluoro-benzylamide;-   95:    4-(2-Amino-5-hydroxymethyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid 3,4-difluoro-benzylamide;-   96:    4-(2-Cyclohexylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid 3,4-difluoro-benzylamide;-   97:    4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (pyridin-4-ylmethyl)-amide;-   98:    4-[5-(3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid 3-trifluoromethyl-benzylamide;-   99:    4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   100:    4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (benzo[1,3]dioxol-5-ylmethyl)-amide;-   101:    4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-dimethylamino-2-pyridin-3-yl-ethyl)-amide;-   102:    4-[2-Amino-5-(3,5-dichloro-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid 4-methanesulfonyl-benzylamide;-   103:    4-[5-(3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (benzo[1,3]dioxol-5-ylmethyl)-amide;-   104:    4-[5-(3,5-Dichloro-phenyl)-2-phenylamino-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-amide;-   105:    4-[2-Amino-5-(3-fluoro-5-trifluoromethyl-phenyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   106: 4-(2-Amino-5-propyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-pyridin-3-yl-ethyl)-amide;-   107: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-pyridin-3′-yl-ethyl)-amide;-   108:    4-(5-Methyl-2-methylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-pyridin-3-yl-ethyl)-amide;-   109: 4-(2-Methylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (2-pyridin-3-yl-ethyl)-amide;-   110:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-dimethylamino-ethyl)-amide;-   111:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid propylamide;-   112:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (3-phenyl-propyl)-amide;-   113:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (naphthalen-1-ylmethyl)-amide;-   114:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid cyclopropylamide;-   115: 4-(2-Ethylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    2-trifluoromethyl-benzylamide;-   116:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   117:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   118: 4-(2-Ethylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (4-methyl-cyclohexyl)-amide;-   119:    4-(5-Ethyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid isopropylamide;-   120:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-amino-ethyl)-amide;-   121: 4-(2-Amino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    benzyl-methyl-amide;-   122: 4-(2-Amino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (2-hydroxy-1-methyl-2-phenyl-ethyl)-methyl-amide;-   123:    1-{4-[4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carbonyl]-piperazin-1-yl}-ethanone;-   124:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (3-phenyl-propyl)-amide;-   125: 4-(2-Amino-5-ethyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    [2-(6-methoxy-1H-indol-3-yl)-ethyl]-amide;-   126:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-phenoxy-ethyl)-amide;-   127:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (1-methyl-3-phenyl-propyl)-amide;-   128:    4-(5-Methyl-2-methylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (1H-benzoimidazol-2-ylmethyl)-amide;-   129:    4-(5-Methyl-2-methylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (1-hydroxymethyl-3-methyl-butyl)-amide;-   130:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [1-hydroxymethyl-2-(1H-imidazol-4-yl)-ethyl]-amide;-   131: 4-(2-Amino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (tetrahydro-furan-2-ylmethyl)-amide;-   132:    4-[2-(2-Diethylamino-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid 3i4-difluoro-benzylamide;-   133:    4-[5-Methyl-2-(2-piperidin-1-yl-quinazolin-4-ylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid benzylamide;-   134:    4-(5-Methyl-2-methylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [1-(3-chloro-4-fluoro-phenyl)-2-hydroxy-ethyl]-amide;-   135:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [1-(3-chloro-4-fluoro-phenyl)-2-hydroxy-ethyl]-amide;-   136:    4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   137:    4-[2-(3-Methoxy-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   138:    4-[2-(3-Hydroxy-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   139:    4-[2-(Benzo[1,3]dioxol-5-ylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   140:    4-[5-Methyl-2-(4-sulfamoyl-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   141:    4-[2-(3-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   142:    4-[2-(4-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   143:    4-(5-Cyclohexyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   144:    4-(5-Cyclopropyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   145:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [1-(3-fluoro-4-methyl-phenyl)-2-hydroxy-ethyl]-amide;-   146:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;-   147:    4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid [1-(3-fluoro-4-methyl-phenyl)-2-hydroxy-ethyl]-amide;-   148:    4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;-   149:    4-[5-Methyl-2-(3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   150:    4-(2-Benzylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   151:    4-[2-(3,4-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   152:    4-[2-(4-Benzyloxy-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   153:    4-(2-Isopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   154:    4-[5-Methyl-2-(2,2,2-trifluoro-ethylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   155:    4-[2-(2-Hydroxy-1-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   156:    4-[2-(2-Methoxy-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   157:    4-[5-Methyl-2-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   158:    4-(2-Isobutylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   159:    4-[2-(Cyclopropylmethyl-amino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   160:    4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   161:    4-(2-Amino-5-methoxymethyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   162:    4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   163:    4-(5-Methyl-2-propylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   164:    4-(5-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   165:    4-(5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   166:    4-[2-(2-Hydroxy-1-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   167:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-methyl-2-phenyl-ethyl)-amide;-   168:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-methyl-2-phenyl-ethyl)-amide;-   169:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-2-phenyl-ethyl)-amide;-   170:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl)-amide;-   171:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl)-amide;-   172:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (3-hydroxy-1-phenyl-propyl)-amide;-   173:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (3-hydroxy-1-phenyl-propyl)-amide;-   174:    4-[2-(1-Hydroxymethyl-cyclopropylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   175:    4-[2-(2-Hydroxy-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   176:    4-[2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   177:    4-[2-(2-Hydroxy-propylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   178:    4-[2-(2-Hydroxy-propylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   179:    4-[2-(2-Hydroxy-cyclohexylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   121:    4-[2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   121:    4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   180: 4-(2-Amino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (2-hydroxy-1-methyl-2-phenyl-ethyl)-methyl-amide;-   181: 4-(2-Amino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (2-hydroxy-1-methyl-2-phenyl-ethyl)-ethyl-amide;-   183: 4-(2-Amino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (2-hydroxy-2-phenyl-ethyl)-methyl-amide;-   184:    {[4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carbonyl]-amino}-phenyl-acetic    acid methyl ester;-   186: 4-(2-Amino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid    (2-hydroxy-1-methyl-2-phenyl-ethyl)-methyl-amide;-   187:    4-(2-Ethylamino-5-methoxymethyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   188:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-pyridin-3-yl-ethyl)-amide;-   189:    4-(2-Ethylamino-5-hydroxymethyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   190:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [1-(3-fluoro-5-trifluoromethyl-phenyl)-2-hydroxy-ethyl]-amide;-   191:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [1-(3-fluoro-phenyl)-2-hydroxy-ethyl]-amide;-   192:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [1-(2-fluoro-phenyl)-2-hydroxy-ethyl]-amide;-   193:    4-[2-(2-Cyclopropyl-1-hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   194:    4-[2-(2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   195:    4-(2-Ethoxyamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   196:    4-[2-(1-Hydroxymethyl-2-methyl-propylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   197:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-oxo-1-phenyl-propyl)-amide;-   198:    4-(2-Ethylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;-   199:    4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;-   200:    4-[2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;-   201:    4-[2-(2-Hydroxy-1-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl)-amide;-   200:    4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;-   202:    4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-amide;-   203:    4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [2-hydroxy-1-(2-methoxy-phenyl)-ethyl]-amide;-   204:    4-(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;-   205:    4–1(2-Cyclopropylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-m-tolyl-ethyl)-amide;-   206:    4-(2-Methoxyamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   207:    4-(2-Isopropoxyamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   208:    4-[2-(3-Dimethylamino-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-m-tolyl-ethyl))-amide;-   209:    4-[2-(2-Chloro-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-m-tolyl-ethyl)-amide;-   210:    4-[2-(2-Hydroxy-1-phenyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-m-tolyl-ethyl)-amide;-   211:    4-[2-(2,3-Dimethyl-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-m-tolyl-ethyl)-amide;-   212:    4-[2-(3-Fluoro-phenylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-m-tolyl-ethyl)-amide;-   213:    4-(2-Acetylamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   214:    4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   215:    4-[5-Methyl-2-(pyridin-3-ylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   216:    4-{5-Methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   217:    4-{5-Methyl-2-((tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   218:    N′-{4-[5-(2-Hydroxy-1-phenyl-ethylcarbamoyl)-1H-pyrrol-3-yl]-5-methyl-pyrimidin-2-yl}-hydrazinecarboxylic    acid ethyl ester;-   219:    4-{5-Methyl-2-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   220:    4-(2-Cyclopropylmethoxyamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   221:    4-[2-(Isoxazol-3-ylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   222:    4-[2-(2-Hydroxy-1-methyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-m-tolyl-ethyl)-amide;-   223:    4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-m-tolyl-ethyl)-amide;-   224:    4-(5-Methyl-2-o-tolylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;-   225:    4-[2-(2-Hydroxy-ethoxyamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   226:    4-[2-(N′,N′-Dimethyl-hydrazino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   227:    4-[5-Methyl-2-(2-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   228:    4-[5-Methyl-2-(morpholin-4-ylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   229:    4-[5-Methyl-2-(5-methyl-isoxazol-3-ylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   230:    4-{2-[1-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethylamino]-5-methyl-pyrimidin-4-yl}-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   231:    4-(5-Methyl-2-phenylamino-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid [1-(3-fluoro-phenyl)-2-hydroxy-ethyl)-amide;-   232:    4-[2-(1-Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;-   233:    4-[2-(2-Hydroxy-1-hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid [1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;-   234:    4-[2-(1-Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-m-tolyl-ethyl)-amide;-   235:    4-[2-(2-Hydroxy-1-hydroxymethyl-ethylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   236:    4-[2-(1-Hydroxymethyl-propylamino)-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide;-   237:    4-[5-Methyl-2-(2-methyl-cyclopropylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide; and-   238:    4-(2-Cyanoamino-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic    acid (2-hydroxy-1-phenyl-ethyl)-amide.

1. A compound of formula I′:

or a pharmaceutically acceptable salt thereof, wherein: Sp is a5-membered heteroaromatic ring selected from pyrrole, imidazole,pyrazole, triazole, oxazole, isoxazole, 1,3-thiazole, 1,2-thiazole, orfuran, wherein Ring A and Q′R^(2′) are attached to Sp at non-adjacentpositions; and wherein Sp has up to two R⁶ substituents, provided thattwo substitutable carbon ring atoms in Sp are not simultaneouslysubstituted by R⁶; Z¹ is CH and Z² is CH; T is a linker group selectedfrom —NH—, —CH₂—, —CO—, or a saturated or unsaturated C₁₋₆ alkylidenechain which is optionally substituted, and wherein up to two saturatedcarbons of the chain are optionally replaced by —C(O)—, —C(O)C(O)—,—CONR⁷—, —CONR⁷NR⁷—, —CO₂—, —OC(O)—, —NR⁷CO₂—, —O—, —NR⁷CONR⁷—,—OC(O)NR⁷—, —NR⁷NR⁷—, —NR⁷CO—, —S—, —SO—, —SO₂—, —NR⁷—, —SO₂NR⁷—, or—NR⁷SO₂—; Q′ is selected from —CO₂—, —C(O)NR⁷— or —SO₂NR⁷—; U isselected from —NR⁷—, —NR⁷CO—, —NR⁷CONR⁷—, —NR⁷CO₂—, —O—, —CONR⁷—, —CO—,—CO₂—, —OC(O)—, —NR⁷SO₂—, —SO₂NR⁷—, —NR⁷SO₂NR⁷—, or —SO₂—; m and n areeach independently selected from zero or one; R¹ is selected fromhydrogen, CN, halogen, R, N(R⁷)₂, OR, or OH; R^(2′) is selected from—(CH₂)_(y)CH(R⁵)₂ or —(CH₂)_(y)CH(R⁸)CH(R⁵)₂; y is 0–6; R³ is selectedfrom R⁷, R, —(CH₂)_(y)CH(R⁸)R, CN, —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, or—(CH₂)_(y)CH(R⁸)N(R⁴)₂; each R is independently selected from anoptionally substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, aheteroaryl ring having 5–10 ring atoms, or a heterocyclyl ring having3–10 ring atoms; each R⁴ is independently selected from R, R⁷, —COR⁷,—CO₂R, —CON(R⁷)₂, —SO₂R⁷, —(CH₂)_(y)R⁵, or —(CH₂)_(y)CH(R⁵)₂; each R⁵ isindependently selected from R, OR, CO₂R, (CH₂)_(y)N(R⁷)₂, N(R⁷)₂, OR⁷,SR⁷, NR⁷COR⁷, NR⁷CON(R⁷)₂, CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, orSO₂N(R⁷)₂; each R⁶ is independently selected from R⁷, F, Cl, OR⁷, SR⁷,NR⁷COR⁷, NR⁷CON(R⁷)₂; CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, or SO₂N(R⁷)₂;each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5–8 membered heterocyclyl orheteroaryl ring; R⁸ is selected from R, (CH₂)_(w)OR⁷, (CH₂)_(w)N(R⁴)₂,or (CH₂)_(w)SR⁷; and each w is independently selected from 0–4.
 2. Thecompound according to claim 1, wherein said compound has one or morefeatures selected from the group consisting of: (a) R³ is hydrogen,carbocyclyl, —CH(R⁸)R, or an optionally substituted group selected fromC₁₋₄ aliphatic, 3–6 membered heterocyclic, or a 5–6 membered aryl orheteroaryl ring; (b) T_(m)R¹ is hydrogen, amino, OH, 3–6 memberedcarbocyclyl, or an optionally substituted group selected from C₁₋₆aliphatic or a 5–6 membered aryl or heteroaryl ring; and (c) R⁵ is R orOR⁷, wherein R is carbocyclic, or an optionally substituted 5 or6-membered aryl or heteroaryl ring.
 3. The compound according to claim2, wherein: (a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, or an optionallysubstituted group selected from C₁₋₄ aliphatic, 3–6 memberedheterocyclic, or a 5–6 membered aryl or heteroaryl ring; (b) T_(m)R¹ ishydrogen, amino, OH, 3–6 membered carbocyclyl, or an optionallysubstituted group selected from C₁₋₆ aliphatic or a 5–6 membered aryl orheteroaryl ring; and (c) R⁵ is R or OR⁷, wherein R is carbocyclic, or anoptionally substituted 5 or 6-membered aryl or heteroaryl ring.
 4. Thecompound according to claim 2, wherein said compound has one or morefeatures selected from the group consisting of: (a) R³ is selected fromhydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl,—CH(CH₂OH)phenyl, —CH(CH₂OH)ethyl, —CH(CH₂OH)₂, —CH(CH₂OH)isopropyl,—CH(CH₂OH)CH₂cyclopropyl, or an optionally substituted phenyl, benzyl,or isoxazolyl group; (b) T_(m)R¹ is selected from optionally substitutedphenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH,OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and (c) R⁵ is OH, CH₂OH,carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q′is —C(O)NH—.
 5. The compound according to claim 4, wherein: (a) R³ isselected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl,isopropyl, —CH(CH₂OH)phenyl, —CH(CH₂OH)ethyl, —CH(CH₂OH)₂,—CH(CH₂OH)isopropyl, —CH(CH₂OH)CH₂cyclopropyl, or an optionallysubstituted phenyl, benzyl, or isoxazolyl group; (b) T_(m)R¹ is selectedfrom optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl,cyclohexyl, CH₂OCH₃, CH₂OH, OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, orCH₂NHCH₃; and (c) R⁵ is OH, CH₂OH, carbocyclic, or an optionallysubstituted phenyl or pyridyl ring, and Q′ is —C(O)NH—.
 6. The compoundaccording to claim 1, wherein said compound is of formula I″:

or a pharmaceutically acceptable salt thereof.
 7. The compound accordingto claim 6, wherein said compound has one or more features selected fromthe group consisting of: (a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, oran optionally substituted group selected from C₁₋₄ aliphatic, 3–6membered heterocyclic, or a 5–6 membered aryl or heteroaryl ring; (b)T_(m)R¹ is hydrogen, N(R⁴)₂, OH, 3–6 membered carbocyclyl, or anoptionally substituted group selected from C₁₋₆ aliphatic or a 5–6membered aryl or heteroaryl ring; and (c) R⁵ is an optionallysubstituted 6-membered aryl, heteroaryl, or carbocyclic ring.
 8. Thecompound according to claim 7, wherein: (a) R³ is hydrogen, carbocyclyl,—CH(R⁸)R, or an optionally substituted group selected from C₁₋₄aliphatic, 3–6 membered heterocyclic, or a 5–6 membered aryl orheteroaryl ring; (b) T_(m)R¹ is hydrogen, N(R⁴)₂, OH, 3–6 memberedcarbocyclyl, or an optionally substituted group selected from C₁₋₆aliphatic or a 5–6 membered aryl or heteroaryl ring; and (c) R⁵ is anoptionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.9. The compound according to claim 1, wherein said compound is offormula I°:

or a pharmaceutically acceptable salt thereof.
 10. The compoundaccording to claim 9, wherein said compound has one or more featuresselected from the group consisting of: (a) R³ is hydrogen, carbocyclyl,—CH(R⁸)R, or an optionally substituted group selected from C₁₋₄aliphatic, 3–6 membered heterocyclic, or a 5–6 membered aryl orheteroaryl ring; (b) T_(m)R¹ is hydrogen, amino, OH, 3–6 memberedcarbocyclyl, or an optionally substituted group selected from C₁₋₆aliphatic or a 5–6 membered aryl or heteroaryl ring; and (c) R⁵ is R orOR⁷, wherein R is carbocyclic, or an optionally substituted 5 or6-membered aryl or heteroaryl ring.
 11. The compound according to claim10, wherein: (a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, or an optionallysubstituted group selected from C₁₋₄ aliphatic, 3–6 memberedheterocyclic, or a 5–6 membered aryl or heteroaryl ring; (b) T_(m)R¹ ishydrogen, amino, OH, 3–6 membered carbocyclyl, or an optionallysubstituted group selected from C₁₋₆ aliphatic or a 5–6 membered aryl orheteroaryl ring; and (c) R⁵ is R or OR⁷, wherein R is carbocyclic, or anoptionally substituted 5 or 6-membered aryl or heteroaryl ring.
 12. Acomposition comprising an effective amount of a compound according toany of claims 1 or 2–11 and a pharmaceutically acceptable carrier. 13.The composition according to claim 12, further comprising an additionaltherapeutic agent selected from a chemotherapeutic agent oranti-proliferative agent, or an agents for treating diabetes, ananti-inflammatory agent, an immunomodulatory or immunosuppressive agent,an agent for treating neurlogical disorders, an agent for treatingcardiovascular disease, an agent for treating liver disease,cholestyramine, an interferon, an anti-viral agents, an agents fortreating blood disorders, or an agent for treating immunodeficiencydisorders.
 14. A method of treating a disease in a patient, wherein thedisease is a cancer selected from melanoma, colon cancer, breast cancer,lung cancer, kidney carcinoma, ovarian cancer, pancreatic cancer, orprostate cancer comprising the step of administering to said patient acomposition according to claim
 12. 15. A method of treating acardiovascular disease in a patient comprising the step of administeringto said patient a composition according to claim 12, wherein saidcardiovascular disease is selected from stroke, restenosis,cardiomegaly, atherosclerosis, myocardial infarction, or congestiveheart failure.
 16. A method of treating a disease in a patient in needthereof, wherein said disease is diabetes, comprising the step ofadministering to said patient a composition according to claim
 12. 17. Amethod of treating a disease in a patient in need thereof, wherein saiddisease is Alzheimer's disease, comprising the step of administering tosaid patient a composition according to claim
 12. 18. A method oftreating a disease in a patient in need thereof, wherein said disease isschizophrenia, comprising the step of administering to said patient acomposition according to claim
 12. 19. A method of treating a cancerselected from melanoma, colon cancer, breast cancer, lung cancer, kidneycarcinoma, ovarian cancer, pancreatic cancer, or prostate cancer, whichmethod comprises administering to said patient a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Sp is a5-membered heteroaromatic ring, selected from pyrrole, imidazole,pyrazole, triazole, oxazole, isoxazole, 1,3-thiazole, 1,2-thiazole, orfuran, wherein Ring A and QR² are attached to Sp at non-adjacentpositions; and wherein Sp has up to two R⁶ substituents, provided thattwo substitutable carbon ring atoms in Sp are not simultaneouslysubstituted by R⁶; Z¹ is CH and Z² is CH; T is a linker group selectedfrom —NH—, —CH₂—, —CO—, or a saturated or unsaturated C₁₋₆ alkylidenechain which is optionally substituted, and wherein up to two saturatedcarbons of the chain are optionally replaced by —C(O)—, —C(O)C(O)—,—CONR⁷—, —CONR⁷NR⁷—, —CO₂—, —OC(O)—, —NR⁷CO₂—, —O—, —NR⁷CONR⁷—,—OC(O)NR⁷—, —NR⁷NR⁷—, —NR⁷CO—, —S—, —SO—, —SO₂—, —NR⁷—, —SO₂NR⁷—, or—NR⁷SO₂—; Q is —CO₂—, —C(O)NR⁷—, or —S(O)₂NR⁷—; U is selected from—NR⁷—, —NR⁷CO—, —NR⁷CONR⁷—, —NR⁷CO₂—, —O—, —CONR⁷—, —CO—, —CO₂—,—OC(O)—, —NR⁷SO₂—, —SO₂NR⁷—, —NR⁷SO₂NR⁷—, or —SO₂—; m and n are eachindependently selected from zero or one; R¹ is selected from hydrogen,CN, halogen, R, N(R⁷)₂, OR, or OH; R² is selected from —(CH₂)_(y)R⁵,—(CH₂)_(y)CH(R⁵)₂, —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, —N(R⁴)₂, or—NR⁴(CH₂)_(y)N(R⁴)₂; y is 0–6; R³ is selected from R⁷, R,—(CH₂)_(y)CH(R⁸)R, CN, —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, or—(CH₂)_(y)CH(R⁸)N(R⁴)₂; each R is independently selected from anoptionally substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, aheteroaryl ring having 5–10 ring atoms, or a heterocyclyl ring having3–10 ring atoms; each R⁴ is independently selected from R, R⁷, —COR⁷,—CO₂R, —CON(R⁷)₂, —SO₂R⁷, —(CH₂)_(y)R⁵, or —(CH₂)_(y)CH(R⁵)₂; each R⁵ isindependently selected from R, OR, CO₂R, (CH₂)_(y)N(R⁷)₂, N(R⁷)₂, OR⁷,SR⁷, NR⁷COR⁷, NR⁷CON(R⁷)₂, CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, orSO₂N(R⁷)₂; each R⁶ is independently selected from R⁷, F, Cl, OR⁷, SR⁷,NR⁷COR⁷, NR⁷CON(R⁷)₂, CON(R⁷)₂, SO₂R⁷, NR⁷SO₂R⁷, COR⁷, CN, or SO₂N(R⁷)₂;each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5–8 membered heterocyclyl orheteroaryl ring; R⁸ is selected from R, (CH₂)_(w)OR⁷, (CH₂)_(w)N(R⁴)₂,or (CH₂)_(w)SR⁷; and each w is independently selected from 0–4.
 20. Themethod according to claim 19, wherein said compound has one or morefeatures selected from the group consisting of: (a) R³ is hydrogen,carbocyclyl, —CH(R⁸)R, or an optionally substituted group selected fromC₁₋₄ aliphatic, 3–6 membered heterocyclic, or a 5–6 membered aryl orheteroaryl ring; (b) T_(m)R¹ is hydrogen, amino, OH, 3–6 memberedcarbocyclyl, or an optionally substituted group selected from C₁₋₆aliphatic or a 5–6 membered aryl or heteroaryl ring; (c) Q is, —CO₂—,—CONH—, or; —SO₂NH—; (d) R² is —NR⁴(CH₂)_(y)N(R⁴)₂, —(CH₂)_(y)R⁵,—(CH₂)_(y)CH(R⁵)₂, or —(CH₂)_(y)CH(R⁸)CH(R⁵)₂; (f) R⁴ is R, R⁷, or—(CH₂)_(y)CH(R⁵)₂; and (g) R⁵ is an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5–6 membered heteroaryl, or 5–6membered heterocyclyl.
 21. The method according to claim 20, wherein:(a) R³ is hydrogen, carbocyclyl, —CH(R⁸)R, or an optionally substitutedgroup selected from C₁₋₄ aliphatic, 3–6 membered heterocyclic, or a 5–6membered aryl or heteroaryl ring; (b) T_(m)R¹ is hydrogen, amino, OH,3–6 membered carbocyclyl, or an optionally substituted group selectedfrom C₁₋₆ aliphatic or a 5–6 membered aryl or heteroaryl ring; (c) Q is—CO₂—, —CONH—, —SO₂NH—, or —SO₂NH—; (d) R² is —NR⁴(CH₂)_(y)N(R⁴)₂,—(CH₂)_(y)R⁵, —(CH₂)_(y)CH(R⁵)₂, or —(CH₂)_(y)CH(R⁸)CH(R⁵)₂; (f) R⁴ isR, R⁷, or —(CH₂)_(y)CH(R⁵)₂; and (g) R⁵ is an optionally substitutedgroup selected from C₁₋₆ aliphatic, phenyl, 5–6 membered heteroaryl, or5–6 membered heterocyclyl.
 22. The method according to claim 20, whereinsaid compound has one or more features selected from the groupconsisting of: (a) R³ is selected from hydrogen, methyl, ethyl, propyl,cyclopropyl, cyclohexyl, isopropyl, —CH(CH₂OH)phenyl, —CH(CH₂OH)ethyl,—CH(CH₂OH)₂, —CH(CH₂OH)isopropyl, —CH(CH₂OH)CH₂cyclopropyl, or anoptionally substituted phenyl, benzyl, or isoxazolyl group; (b) T_(m)R¹is selected from optionally substituted phenyl, methyl, ethyl, propyl,cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, OH, NH₂, NHCH₃, NHAc,NHC(O)NHCH₃, or CH₂NHCH₃; (c) Q is —CONH—, or —SO₂NH—; (d) R² is—(CH₂)_(y)R⁵, —(CH₂)_(y)CH(R⁵)₂, or —(CH₂)_(y)CH(R⁸)CH(R⁵)₂, wherein R⁸is OH or CH₂OH; and (e) R⁵ is —CH₂OH, —(CH₂)₂OH, isopropyl, or anoptionally substituted group selected from pyrrolidin-1-yl,morpholin-4-yl, piperidin-1-yl, piperazin-1-yl,4-methyl[1,4]diazepan-1-yl, 4-phenyl-piperazine1-yl, pyridin-3-yl,pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline,tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl.
 23. The methodaccording to claim 22, wherein: (a) R³ is selected from hydrogen,methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl,—CH(CH₂OH)phenyl, —CH(CH₂OH)ethyl, —CH(CH₂OH)₂, —CH(CH₂OH)isopropyl,—CH(CH₂OH)CH₂cyclopropyl, or an optionally substituted phenyl, benzyl,or isoxazolyl group; (b) T_(m)R¹ is selected from optionally substitutedphenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH,OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; (c) Q is —CONH—, or—SO₂NH—; (d) R² is —(CH₂)_(y)R⁵, —(CH₂)_(y)CH(R⁵)₂, or—(CH₂)_(y)CH(R⁸)CH(R⁵)₂, wherein R⁸ is OH or CH₂OH; and (e) R⁵ is—CH₂OH, —(CH₂)₂OH, isopropyl, or an optionally substituted groupselected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl,piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl-piperazine-1-yl,pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl,1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl,phenyl, or benzyl.
 24. A composition for coating an implantable devicecomprising a compound according to claim 1 and a carrier suitable forcoating said implantable device.
 25. An implantable device coated with acomposition according to claim 24.